Pyrrole derivatives and medicinal composition

ABSTRACT

The invention relates to a pharmaceutical composition comprising a pyrrole derivative of the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate of either of them, as an active ingredient. ##STR1## (wherein R 1  represents hydrogen or alkoxycar91 bonylamino, R 2  represents alkyl, aryl which may be substituted, aromatic heterocyclyl which may be substituted, unsubstituted amino, monoalkylamino, dialkylamino, or cyclic amino which may be substituted; R 3  represents cyano or carbamoyl; R 4  represents hydrogen or alkyl; E represents alkylene; q is equal to 0 or 1, A represents methyl, aryl which may be substituted, or aromatic heterocyclyl which may be substituted). The pharmaceutical composition of the invention is effective for the treatment of pollakiuria or urinary incontinence.

This application is a 371 of PCT/JP96/01526 filed on Jun. 6, 1996.

TECHNICAL FIELD

The present invention relates to a pyrrole derivative, a pharmaceutically acceptable salt thereof, and a solvate of either of them, all of which are useful as medicines.

The compound of the invention has urinary bladder capacity increasing activity and is useful for the treatment of pollakiuria and urinary incontinence.

BACKGROUND ART

The frequency of urination of healthy humans is generally 4-6 times a day and usually no urine is voided during sleep at night. The condition of an abnormally increased frequency of urination is called pollakiuria and the condition of involuntary emptying of the urinary bladder is known as urinary incontinence. Both morbidities are bothersome to the affected person because sleep is disturbed and going out is restricted. The frequency of occurring pollakiuria or urinary incontinence is particularly high in the bedridden aged persons and patients with dementia and there is a pressing need for development of useful therapeutic drug in this field, not only for patients and clinical doctors but also for the people taking charge of nursing care.

As therapeutic drugs designed to ameliorate pollakiuria and urinary incontinence through increase in bladder capacity, flavoxate, oxybutynin, propiverine and so on are used today.

Meanwhile, as pyrrole derivatives apparently resembling the compound of the present invention, the compounds listed below in Table 1 are known. However, none of them are known to have the first medicinal use, namely, to be useful for the treatment of disease such as pollakiuria or urinary incontinence.

                                      TABLE 1                                      __________________________________________________________________________     Compound                                                                         No. Structural formula Literature                                            __________________________________________________________________________        R1                                                                                                        J. Prakt. Chem., 318, 663 (1976).                   -  R2                                                                                                     J. Heterocyclic Chem., 14, 383 (1977),  Z.                                   Chem., 1, 349 (1961).                                 -  R3                                                                                                     J. Heterocyclic Chem., 14, 383 (1977).                                         -  R4                                                                          J. Heterocyclic Chem., 14, 383 (1977).                                         -  R5                                                                          Khim. Geterotsiki. Soedim., (9), 1217,                                       (1975)  (Chem. Abstr., 84, 59299 (1976))                                         -  R6                                                                          J. Heterocyclic Chem., 14, 383 (1977).                                         -  R7                                                                          Khim. Geterotsiki. Soedim., (9), 1217,                                       (1975)  (Chem. Abstr., 84, 59299 (1976))                                         -  R8                                                                          J. Pharm. Sci., 68, 317 (1979).                     -  R9                                                                                                     Synthesis, 217 (1979).                              - R10                                                                                                     Synthesis, 55 (1974).                               - R11                                                                                                     J. Pharm. Sci., 65, 908 (1976).  J.                                          Heterocyclic Chem., 23, 397 (1986).                   - R12                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R13                                                                                                     Khim. Geterotsiki. Soedim., (9), 1217,                                       (1975)  (Chem. Abstr., 84, 59299 (1976))                                         - R14                                                                          J. Heterocyclic Chem., 14, 383 (1977).                                         - R15                                                                          Khim. Geterotsiki. Soedim., (9), 1217,                                       (1975)  (Chem. Abstr., 84, 59299 (1976))                                         - R16                                                                          Farmaco, Ed. Sc., 43, 103 (1988).                   - R17                                                                                                     Farmaco, Ed. Sc., 43, 103, (1988).                  - R18                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R19                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R20                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R21                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R22                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R23                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R24                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R25                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R26                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R27                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R28                                                                                                     Farmaco, Ed. Sc., 43, 103 (1988).                   - R29                                                                                                     J. Chem. Res., Synop. (8), 266 (1992).  J.                                   Chem. Res., Miniprint, 2049 (1992).                   - R30                                                                                                     Heterocycles, 10, 261 (1978).                       - R31                                                                                                     Heterocycles, 10, 261 (1978).                       - R32                                                                                                     J. Org. Chem., 43, 4273 (1978).  J. Chem.                                    Soc., B, (1), 79 (1970).                              - R33                                                                                                     J. Org. Chem., 43, 4273 (1978).                     - R34                                                                                                     J. Org. Chem., 43, 4273 (1978).  EP 358047                                   A2.                                                   - R35                                                                                                     J. Org. Chem., 43, 4273 (1978).                     - R36                                                                                                     J. Org. Chem., 43, 4273 (1978).                     - R37                                                                                                     J. Org. Chem., 43, 4273 (1978).  Heterocycle                                 s, 20, 829 (1983).                                    - R38                                                                                                     J. Chem. Soc., B, (1), 79 (1970).                   - R39                                                                                                     Gazz. Chim. Ital., 71, 375 (1941).                  - R40                                                                                                     Justus Liebigs Ann. Chem., 447, 43 (1926).                                     - R41                                                                          WO 93/19067.                                        - R42                                                                                                     EP 480204 A1.                                       - R43                                                                                                     EP 314009 A2.  EP 389904 A2.                        - R44                                                                                                     Chem. Ber., 105, 1258 (1972).                       - R45                                                                                                     J. Org. Chem., 31, 4110 (1996).                     - R46                                                                                                     J. Org. Chem., 31, 4110 (1996).                     - R47                                                                                                     EP 389904 A2.                                       - R48                                                                                                     EP 389904 A2.                                       - R49                                                                                                     EP 389904 A2.                                    __________________________________________________________________________

DISCLOSURE OF INVENTION

The inventors of the present invention did much research for developing a drug which is structurally different from the hitherto-known therapeutic drugs for pollakiuria or urinary incontinence and is more useful than those drugs.

As a result, the inventors found that the pyrrole derivative of the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate of either of them, has excellent bladder capacity increasing activity and is useful as a therapeutic drug for pollakiuria or urinary incontinence. The present invention has been completed on the basis of the above finding. ##STR51##

wherein R¹ represents hydrogen or alkoxycarbonylamino;

R² represents (1) alkyl, (2) aryl which may be substituted, (3) aromatic heterocyclyl which may be substituted, ##STR52##

R⁶ and R⁷ may be the same or different and each represents (1) hydrogen or (2) alkyl (which alkyl may be substituted by (1) hydroxyl, (2) aryl which may be substituted by alkoxy, or (3) aromatic heterocyclyl);

Z¹ and Z² may be the same or different and each represents --CH₂ -- or >C═O; provided that Z¹ and Z² do not concurrently represents >C═O;

Y represents --CH₂ --, --O--, --S--, or >NR⁹ ;

R⁹ represents hydrogen, alkyl, acyl, aryl, or aromatic heterocyclyl;

m represents an integer of 1-3; n represents an integer of 0-2; p represents 0 or 1;

in case R² represents aryl which may be substituted or aromatic heterocyclyl which may be substituted, the aryl or aromatic heterocyclyl may be substituted by 1 member or 2-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy may be substituted by halogen, aryl which may be substituted by alkoxy, or alkoxy), (8) --NHSO₂ R⁸², and (9) --NR⁸³ R⁸⁴ ; or two adjacent substituent groups may jointly represent --O--(CH₂)_(t) --O--;

R⁸² represents (1) alkyl or (2) aryl which may be substituted by alkyl;

t represents 1 or 2;

R⁸³ and R⁸⁴ may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R⁸³ and R⁸⁴ jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;

R³ represents cyano or carbamoyl;

R⁴ represents hydrogen or alkyl;

E represents alkylene; q represents 0 or 1;

A represents (1) methyl; (2) aryl which may be substituted, or (3) aromatic heterocyclyl which may be substituted;

in case A represents aryl which may be substituted or aromatic heterocyclyl which may be substituted, the aryl or aromatic heterocyclyl may be substituted by 1 member or 2-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy may be substituted by halogen, aryl which may be substituted by alkoxy, or alkoxy), (8) --NHSO₂ R⁹², and (9) --NR⁹³ R⁹⁴ ; or two adjacent substituent groups may jointly represent --O--(CH₂)_(u) --O--;

R⁹² represents (1) alkyl or (2) aryl which may be substituted by alkyl;

u represents 1 or 2;

R⁹³ and R⁹⁴ may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R⁹³ and R⁹⁴ jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;

A-(E)q, R⁴, and the double bond of the pyrrole ring may jointly, i.e. ##STR53## represent ##STR54##

X represents --O--, --S--, or >NR⁹⁰ where R⁹⁰ represents alkyl;

R⁹⁵, R⁹⁶ and R⁹⁷ may be the same or different and each is selected from the group consisting of (1) hydrogen, (2) halogen, (3) alkyl which may be substituted by halogen, (4) cyano, (5) nitro, (6) alkoxycarbonyl, (7) hydroxy, (8) alkoxy (which alkoxy may be substituted by halogen, or alkoxy), (9) --NHSO₂ R⁹² (R⁹² is as defined above), and (10) --NR⁹³ R⁹⁴ (R⁹³ and R⁹⁴ are as defined above); any two adjacent substituent groups among R⁹⁵, R⁹⁶, and R⁹⁷ may jointly represent --O--(CH₂)_(u) --O-- (u is as defined above).

The present invention relates to a pharmaceutical composition comprising the compound of formula [1] as an active ingredient. The present invention further relates to the compound of formula [1].

Depending on the combination of specific substituent groups, the compound of formula [1] includes known compounds. However, it was discovered for the first time by the inventors of the present invention that those known compounds have bladder capacity increasing activity.

Thus, among pyrrole derivatives of formula [1], the following compounds (1)-(28) are known compounds, while the other compounds are novel compounds not described in any literature.

(1) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl, phenyl, or 4-hydroxyphenyl,

(2) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, --(E)q-- is --CH₂ --, and A is methyl, phenyl, 4-hydroxyphenyl, 4-chlorophenyl, or 3-indolyl,

(3) the compound in which R¹ is hydrogen, R² is morpholino, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl, or phenyl,

(4) the compound in which R¹ is hydrogen, R² is 1-pyrrolidinyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl, 4-bromophenyl, 4-nitrophenyl, or 2,4-dimethylphenyl,

(5) the compound in which R¹ is hydrogen, R² is 1-piperidinyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl or 4-bromophenyl,

(6) the compound in which R¹ is hydrogen, R² is diethylamino, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl, phenyl, 4-bromophenyl, or 3-nitrophenyl,

(7) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, --(E)q-- is --CH₂ CH₂ --, and A is methyl,

(8) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is n-propyl, --(E)q-- is --CH₂ CH₂ --, and A is methyl,

(9) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, --(E)q-- is --CH(CH₃)CH₂ --, and A is methyl,

(10) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is ethyl, q is equal to 0, and A is methyl,

(11) the compound in which R¹ is hydrogen, R² is methylamino, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl,

(12) the compound in which R¹ is hydrogen, R² is 2-oxopyrrolidin-1-yl, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl,

(13) the compound in which R¹ is hydrogen, R² is 1-piperidinyl, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is phenyl,

(14) the compound in which R¹ is hydrogen, R² is n-butylamino, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl,

(15) the compound in which R¹ is hydrogen, R² is methyl, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl or phenyl,

(16) the compound in which R¹ is hydrogen, R² is methyl, R³ is carbamoyl, R⁴ is methyl, q is equal to 0, and A is methyl,

(17) the compound in which R¹ is hydrogen, R² is methyl, R³ is carbamoyl, R⁴ is hydrogen, q is equal to 0, and A is methyl or phenyl,

(18) the compound in which R¹ is hydrogen, R² is methyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl or phenyl,

(19) the compound in which R¹ is hydrogen, R² is methyl, R³ is cyano, R⁴ is hydrogen, --(E)q-- is --CH(CH₃)CH₂ --, and A is methyl,

(20) the compound in which R¹ is hydrogen, R² is phenyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl or phenyl,

(21) the compound in which R¹ is hydrogen, R² is isobutyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl,

(22) the compound in which R¹ is hydrogen, R² is 4-methoxycarbonylphenyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl,

(23) the compound in which R¹ is hydrogen, R² is 4-methoxycarbonylphenyl, R³ is cyano, R⁴ is hydrogen, --(E)q-- is --CH₂ --, and A is methyl,

(24) the compound in which R¹ is hydrogen, R² is 2-thienyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is 2-thienyl or 2-furyl,

(25) the compound in which R¹ is hydrogen, R² is 4-nitrophenyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl,

(26) the compound in which R¹ is hydrogen, R² is 1-isoquinolyl, R³ is cyano or carbamoyl, R⁴ is hydrogen, q is equal to 0, and A is phenyl,

(27) the compound in which R¹ is hydrogen, R² is 2-furyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is 2-thienyl or 2-furyl,

(28) the compound in which R¹ is hydrogen, R² is methyl, R³ is cyano, R⁴ is methyl, --(E)q-- is --CH₂ --, and A is methyl.

The alkyl in formula [1] includes straight-chain or branched alkyl group of 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

The aryl includes aryl group of 6-12 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 3-biphenyl, or 4-biphenyl.

The aromatic heterocyclyl includes aromatic 5- or 6-membered heterocyclic group containing 1-4 hetero-atoms selected from among nitrogen, oxygen and sulfur, and the corresponding benzologue (benzene-fused) systems (provided that 2-pyrrolyl and 3-pyrrolyl are excluded), such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-tetrazolyl, 2-furyl, 3-furyl, 2-benzofuranyl, 3-benzofuranyl, 2-thienyl, and 3thienyl.

The alkylene includes straight-chain or branched alkylene group of 1-4 carbon atoms, such as the following: ##STR55##

The alkyl moiety of said alkoxy, alkoxycarbonyl, or alkoxycarbonylamino includes the alkyl group mentioned above by way of example.

The halogen includes fluorine, chlorine, bromine, and iodine.

The acyl includes acyl group of 1-7 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isohexanoyl, or benzoyl.

The 5- through 7-membered cyclic amino represented by NR⁸³ R⁸⁴ or NR⁹³ NR⁹⁴ includes 1-pyrrolidinyl, 1-piperidinyl, and 1-hexamethyleneimino, among others.

Preferred species of the compound [1] of the invention include those in which R² is ##STR56##

Still more preferred species of compound [1] according to the present invention are those in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is hydrogen or alkyl, q is equal to 0, and A is aryl which may be substituted or aromatic heterocyclyl which may be substituted.

Particularly preferred species of compound [1] according to the present invention are the following compounds (1)-(6).

(1) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is phenyl,

(2) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is 2-fluorophenyl,

(3) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is 2,5-difluorophenyl,

(4) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is 3-pyridyl,

(5) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl,

(6) the compound in which R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is 4-fluorophenyl.

The compound [1] according to the present invention can be produced, for example, by the following processes.

Synthetic Process A (production of compound [1a] corresponding to formula [1] wherein R¹ is hydrogen and R² is ##STR57## [In the above reaction schema, A, E, q, R³, and R⁴ are as defined hereinbefore; R²¹ represents ##STR58## R⁶, R⁷, Z¹, Z², Y, m, n, and p are as defined hereinbefore; L represents halogen such as chlorine, bromine, or iodine]

Compound [1a] can be synthesized by reacting compound [3] with compound [4].

This reaction can be generally carried out in a solvent that does not interfere with the reaction (e.g. alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and ethyl acetate and mixture of such solvents), either in the presence of a base (e.g. ammonia, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, pyridine, 4-dimethylaminopyridine, triethylamine) or in the absence of the base, at -20 to 100° C. The reaction time is dependent on the species of compound [3] and compound [4] used and the reaction temperature but may generally range from 1 minute to 24 hours. The molar ratio of compound [4] to compound [3] is generally 1-2:1. Compound [4] may be used in excess so that it may function as the base as well.

Synthesis Process B (production of compound [1b] corresponding to formula [1] wherein R¹ is hydrogen and R² is NH₂) ##STR59## [In the above reaction schema, A, E, q, R³, and R⁴ are as defined above; R¹⁰ represents alkyl such as that mentioned hereinbefore]

Compound [1b] can be synthesized by reacting compound [5] with compound [6].

This reaction is generally carried out in a solvent that does not interfere with the reaction (e.g. alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, and, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and mixture of such solvents), within the pH range of 9.5-10.5 as adjusted by addition of a base (e.g. a sodium alkoxide such as sodium methoxide or sodium ethoxide, piperidine, trimethylamine, 30-60% aqueous solution of sodium hydroxide, 30-60% aqueous solution of potassium hydroxide) at -10 to 100° C. The reaction time is dependent on the species of compound [5] and compound [6] and the reaction temperature but may generally range from 5 minutes to 24 hours. The molar ratio of compound [6] to compound [5] is generally 1-2:1.

Synthesis Process C (production of compound [1c] corresponding to formula [1] wherein R¹ is alkoxycarbonyl amino and R² is ##STR60## [In the above reaction schema, A, E, q, R²¹, R³, and R⁴ are as defined hereinbefore; R⁵ represents a straight-chain or branched alkyl group of 1-4 carbon atoms]

Compound [1c] can be synthesized by reacting compound [7] with compound [8] in the known manner (J. Heterocyclic Chem., 17, 1793, 1980) and subjecting the reaction product further to reaction with compound [4].

The reaction of compound [7] with compound [8] can be generally carried out in a solvent which does not interfere with the reaction (e.g. ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and mixture of such solvents), either in the presence of a catalytic amount of an acid (e.g. concentrated hydrochloric acid, zinc chloride, boron trifluoride) or in the absence of the acid, 0-150° C., while the byproduct water is continuously distilled off.

To this reaction mixture is added compound [4] at 10-30° C. and the whole mixture is heated at 40-100° C. The reaction time depends on the species of compound [7], compound [8], and compound [4] used and the reaction temperature but may generally range from 30 minutes to 24 hours. The proportions of compound [8] and compound [4] are generally 1-2.2 molar equivalents based on compound [7].

Synthesis Process D (production of compound [1d] corresponding to formula [1] wherein R¹ is alkoxycarbonylamino and R² is NH₂) ##STR61## [In the above reaction schema, A, E, q, R³, R⁴, R⁵, and L are as defined hereinbefore]

Compound [1d] can be synthesized by reacting compound [9] with compound [8] in the known manner (J. Prakt. Chem., 318, 663, 1976).

This reaction can be generally carried out in a solvent which does not interfere with the reaction (e.g. alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), and mixture of such solvents), at 20-100° C. The reaction time is dependent on the species of compound [9] and compound [8] and the reaction temperature but may generally range from 30 minutes to 24 hours. The molar ratio of compound [8] to compound [9] is generally 1-1.2:1.

Synthesis Process E (production of compound [1d] corresponding to formula [1] wherein R¹ is alkoxycarbonylamino and R² is NH₂) ##STR62## [In the above reaction schema, A, E, q, R³, R⁴, and R⁵ are as defined hereinbefore]

Compound [1d] can be synthesized by reacting compound [7] with compound [8] and subjecting the reaction product further reaction with compound [6].

Except that compound [6] is used in lieu of compound [4], the reaction can be carried out in the similar manner as in Synthetic Process C.

Starting with the compound [1f] corresponding to compound [1] of the invention wherein R² is NH₂, which is synthesized by the above Synthetic Processes A-E, the compound in which R² is alkyl-substituted amino can be synthesized by the following Synthetic Process F or Synthetic Process G.

Synthesis Process F (production of compound [1g] corresponding to formula [1] wherein R² is monoalkylamino and compound [1h] corresponding to formula [1] wherein R² is dialkylamino) ##STR63## [In the above reaction schemes, A, E, q, R¹, R³, and R⁴ are as defined hereinbefore. R⁶¹ and R⁷¹ may be the same or different and each represents alkyl such as that mentioned hereinbefore (which alkyl may be substituted by (1) hydroxy, (2) aryl which may be substituted by alkoxy, or (3) aromatic heterocyclyl). R⁶¹⁰ and R⁷¹⁰ represent residues available upon elimination of the bonding-end --CH₂ -- from R⁶¹ and R⁷¹, respectively]

Compound [1g] can be synthesized by reacting compound [1f] with aldehyde [9a] and then reducing the reaction product. Compound [1h] can be synthesized from compound [1g] and aldehyde [9b] in the similar manner.

The reaction of compound [1f] with aldehyde [9a] can be generally carried out in the absence of a solvent or in a solvent which does not interfere with the reaction (e.g. ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), and mixtures of such solvents), either in the presence of a dehydrating agent (e.g. magnesium sulfate, sodium sulfate, active calcium sulfate, molecular sieves) or in the absence of the dehydrating agent, at 0-150° C. The reaction time is dependent on the species of compound [1f] and aldehyde [9a] and the reaction temperature but may generally range from 30 minutes to 120 hours. The molar ratio of compound [9a] to compound [1f] is generally 1-1.2:1.

The reduction reaction can be carried out using a reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent which does not interfere with the reaction (e.g. methanol, ethanol, isopropanol, DMF, DMSO, acetonitrile, or ethyl acetate, or a mixture thereof) at -10 to 40° C. The reaction time is dependent on the species of compound [1f], aldehyde [9a], and reducing agent used and the reaction temperature but may generally range from 30 minutes to 24 hours. The proportion of the reducing agent is generally 1-10 moles per mole of compound [1f].

In carrying out this synthetic process, an orthoformic ester (e.g. methyl orthoformate, ethyl orthoformate) can be used in lieu of formaldehyde (compound [9a] (R⁶¹⁰ ═H), compound [9b] (R⁷¹⁰ ═H)).

Synthesis Process G (production of compound [1i] corresponding to formula [1] wherein R² is 2-oxocyclic amino (Y is --CH₂ --)) ##STR64## [In the above reaction schema, A, E, q, R¹, R³, and R⁴ are as defined hereinbefore; L¹ and L² may be the same or different and each represents halogen such as chlorine, bromine, or iodine; v represents an integer of 3-5.

Compound [1i] can be synthesized by reacting compound [1f] with compound [10].

In this reaction, the acyl halide moiety of compound [10] undergoes reaction in the first place and the alkyl halide moiety then undergoes reaction.

The reaction of the acyl halide moiety can be generally carried out in a solvent which does not interfere with the reaction (e.g. ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and mixture of such solvents), in the presence of a base (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, pyridine, 4-dimethylaminopyridine, trimethylamine) at -78 to 100° C. The reaction time is dependent on the species of compound [1f] and compound [10] and the reaction temperature but may generally range from 30 minutes to 24 hours. The molar ratio of compound [10] to compound [1f] is 1-1.2:1. The proportion of the base is generally 1-10 moles per mole of compound [1f].

The reaction of the alkyl halide moiety is carried out using the compound obtained in the previous step and a strong base (e.g. potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride) in a solvent which does not interfere with the reaction (e.g. alcohols such as methanol and ethanol, ethers such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and mixture of such solvents) at 0-100° C. The reaction time is dependent on the species of compound [1f] and compound [10] and the reaction temperature but may generally range from 30 minutes to 24 hours. The proportion of the strong base is generally 14 1.2 molar equivalents based on compound [1f].

Synthesis Process H (production of compound [1j] corresponding to formula [1] wherein R¹ is hydrogen, R² is (1) alkyl, (2) aryl which may be substituted, or (3) aromatic heterocyclyl which may be substituted, and R⁴ is hydrogen) ##STR65## [In the above reaction schema, A, E, q, R³, and L are as defined hereinbefore; R²² represents (1) alkyl such as that defined hereinbefore, (2) optionally substituted aryl such as that defined hereinbefore, or (3) optionally substituted aromatic heterocyclyl aryl such as that defined hereinbefore]

Compound [1j] can be synthesized by reacting compound [11] with compound [12] in the presence of an acid anhydride (e.g. acetic anhydride, propionic anhydride, an anhydride of A--(E)q--CO₂ H).

This reaction is generally carried out using the above-mentioned acid anhydride as solvent at 0-160° C. The reaction time is dependent on the species of compound [11] and compound [12] and the reaction temperature but may generally range from 5 minutes to 24 hours. The molar ratio of compound [12] to compound [11] is 10-20:1. The proportion of the said acid anhydride is generally 10-100 moles per mole of compound [11].

Synthesis Process I (production of compound [1k] corresponding to formula [1] wherein R² is (1) alkyl, (2) aryl which may be substituted, or (3) aromatic heterocyclyl which may be substituted, and R³ is cyano) ##STR66## [In the above reaction schema, A, E, q, R¹, R⁴, and R²² are as defined hereinbefore]

Compound [1k] can be synthesized by reacting compound [13] with either compound [14] or its acid addition salt.

This reaction can be generally carried out in a solvent which does not interfere with the reaction (e.g. alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol, ethers solvent such as tetrahydrofuran (THF) and diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as benzene, toluene and n-hexane, polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and mixture of such solvents), either in the presence of an acid catalyst (e.g. acetic acid, p-toluenesulfonic acid) or in the absence of the acid, at -20 to 160° C. The reaction time is dependent on the species of compound [13] and compound [14] and the reaction temperature but may generally range from 5 minutes to 18 hours. The molar ratio of compound [14] to compound [13] is generally 1-5:1. The proportion of the acid catalyst is generally 0.1-2 moles per mole of compound [13]. The acid catalyst (such as acetic acid) may be used in excess so that it may function as the solvent as well.

Referring to species of compound [1] wherein R³ is cyano, this R³ can be converted to carbamoyl by the known procedure.

With regard to species of compound [1] wherein R² and A respectively represent nitro-substituted aryl or nitro-substituted aromatic heterocyclyl, the nitro can be converted to amino by the known procedure.

Compound [1] can be isolated and purified from the reaction mixture by conventional separation-purification techniques such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, and ion exchange chromatography as used selectively in a suitable combination.

Any species of compound [1] of the invention that is basic can be used in the form of a free base as a medicine but may be converted to a pharmaceutically acceptable salt by the per se known method and used as such. The salt includes salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and salts with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid.

The hydrochloride, for instance, can be obtained by dissolving compound [1] in alcoholic hydrochloric acid.

There are cases in which a solvate (inclusive of hydrate) of the compound [1] or salt of the invention is available upon recrystallization of the solvated compound from the corresponding solvent or an appropriate solvent mixture containing the corresponding solvent. Such solvates also fall within the scope of the invention.

For instance, there is the case that the hydrate of compound [1] according to the invention is obtained upon recrystallization of compound [1] from an aqueous alcohol.

Compound [1] of the invention may show polymorphism and in such cases the respective polymorphs also fall within the scope of the invention.

The compound [3] through compound [14], which are used as starting compounds in the production of compound [1] of the invention are either known compounds or compounds which can be prepared by the similar process to per se known processes as described in Reference Examples which appear hereinafter.

The compound of the invention is useful as a medicine. As can be understood from the Test Examples presented hereinafter, the compound of the invention has potent bladder capacity increasing activity and is useful particularly as a therapeutic drug for pollakiuria or urinary incontinence.

In the administration of the compound of the invention as a medicine, the compound can be administered either as it is or in the form of a pharmaceutical composition containing 0.1-99.5%, preferably 0.5-90%, of the compound in a pharmaceutically acceptable, nontoxic and inert carrier, to animals including humans.

The carrier includes solid, semisolid or liquid diluents, fillers and other formulation auxiliaries and they may be used either solely or jointly. The pharmaceutical composition is preferably administered in unit dosage forms. The pharmaceutical composition of the invention can be administered intravenously, orally, into the tissue, topically (e.g. transdermally), or rectally. Of course, the dosage form suited to each route of administration should be selected. Oral administration is particularly advantageous.

The dosage of the pharmaceutical composition of the invention for the treatment of pollakiuria or urinary incontience is preferably established in consideration of patient factors, e.g. age and body weight, route of administration, nature and severity of disease, etc. Usually, however, the daily dose as an effective amount of the compound of the invention for adult patients is 0.1-1000 mg/patient, preferably 1-500 mg/patient.

Lower doses may be sufficient in some cases and higher doses may be needed in other cases. The above dosage may be administered in 2-3 divided doses a day.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples, Test Examples and Formulation Examples for the pharmaceutical composition of the invention are further illustrative of the present invention.

REFERENCE EXAMPLE 1 2-Bromo-2',5'-difluoropropiophenone

To a solution of 2',5'-difluoropropiophenone (2.12 g) in diethyl ether (20 ml) under ice-cooling was added bromine dropwise, and the mixture was stirred at room temperature overnight. To this reaction mixture was added ice and the diethyl ether layer was separated, followed by washing with water and saturated aqueous solution of sodium hydrogen carbonate in that order and dried over anhydrous magnesium sulfate (MgSO₄). The either layer was concentrated under reduced pressure to provide the title compound.

The following compounds were synthesized by substantially the same procedure as Reference Example 1.

2-Bromo-4'-ethoxyacetophenone, Bromomethyl 3-thienyl ketone,

2-Bromo-3,4'-methylenedioxyacetophenone,

2-Bromo-2',4'-difluoroacetophenone,

2-Bromo-2',5'-difluoroacetophenone,

2-(Bromoacetyl)benzofuran,

2-Bromo-4'-methanesulfonamidoacetophenone,

2-Bromoacetophenone,

2-Bromo-4'-methoxyacetophenone,

2-Bromo-4'-chloroacetophenone,

2-Bromo-4'-bromoacetophenone,

2-Bromo-4'-nitroacetophenone,

2-Bromo-4'-methylacetophenone,

2-Bromo-3'-methoxyacetophenone,

2-Bromo-2'-methoxyacetophenone,

Bromomethyl 2-thienyl ketone,

2-Bromo-3'-ethoxyacetophenone,

2-Bromo-4'-phenylacetophenone,

2-Bromo-3',4'-dichloroacetophenone,

2-Bromo-4'-fluoroacetophenone,

3-(Bromoacetyl)pyridine,

2-Bromo-4'-isopropoxyacetophenone,

2-(Bromoacetyl)naphthalene,

2-Bromo-3'-chloroacetophenone,

2-Bromo-3'-methyl-4'-chloroacetophenone,

2-(Bromoacetyl)pyridine,

Bromoacetone,

(1-Bromoethyl) methyl ketone,

2-Bromo-4'-n-propoxyacetophenone,

2-Bromo-4'-(2-methoxyethoxy)acetophenone,

2-Bromo-4'-(2-ethoxyethoxy)acetophenone,

2-Bromo-4'-benzyloxyacetophenone,

2-Bromo-2'-fluoroacetophenone,

2-Bromo-3'-fluoroacetophenone,

2-Bromo-4'-trifluoromethylacetone,

2-Bromo-2'-trifluoromethylacetone,

2-Bromo-3'-(2-methoxyethoxy)acetophenone,

2-(Bromoacetyl)furan,

2-Bromo-3'-fluoro-4'-methoxyacetophenone,

2-Bromo-2'-fluoro-4'-methoxyacetophenone,

2-Bromo-4'-(2-fluoroethoxy)acetophenone,

2-Bromo-3'-(2-fluoroethoxy)acetophenone,

2-Bromo-5'-bromo-2',4'-diethoxypropiophenone,

2-Bromo-2'-ethoxypropiophenone,

2-Bromo-4'-isopropoxypropiophenone,

2-Bromo-3,5'-ditrifluoromethylpropiophenone,

2-Bromo-2'-fluoropropiophenone,

2-Bromopropiophenone,

2-Bromo-4'-fluoropropiophenone,

2-Bromo-3'-nitropropiophenone,

2-Bromo-3'-chloropropiophenone,

2-Bromo-4'-methylpropiophenone,

2-Bromo-2',5'-dichloropropiophenone,

2-Bromo-3'-nitroacetophenone,

2-Bromo-1-(2-pyridyl)-1-propanone,

2-Bromo-1-(2-naphthyl)-1-propanone,

2-Bromo-4'-methylpropiophenone,

2-Bromo-1-(3-pyridyl)-1-propanone,

2-Bromo-1-(2-thienyl)-1-propanone,

2-Bromo-3',4'-dichloropropiophenone,

2-Bromo-4'-chloropropiophenone,

2-Bromo-4'-bromopropiophenone,

2-Bromo-4'-benzyloxypropiophenone,

2-Bromo-4'-ethoxypropiophenone,

2-Bromo-4'-hydroxypropiophenone,

2-Bromo-2',5'-dimethoxypropiophenone,

2-Bromo-3'-bromopropiophenone,

2-Bromo-2'-methoxylpropiophenone,

2-Bromo-3',4'-methylenedioxypropiophenone,

2-Bromo-2',4'-dichloropropiophenone,

2-Bromo-1-(2-furyl)-1-propanone,

2-Bromo-1-(4-pyridyl)-1-propanone,

3-Bromo-4-chromanone,

2-Bromo-2'-chloropropiophenone,

2-Bromo-2'-methoxypropiophenone,

2-Bromo-2',5'-difluoropropiophenone,

2-Bromo-2'-methylpropiophenone,

2-Bromo-2',6'-difluoropropiophenone,

2-Bromo-4'-trifluoromethylpropiophenone,

2-Bromo-3'-trifluoromethylpropiophenone,

2-Bromo-3'-methoxycarbonylpropiophenone,

2-Bromo-5'-fluoro-2'-methoxypropiophenone.

REFERENCE EXAMPLE 2 2-Cyanoacetamidine

To saturated ammonia/ethanol (20 ml) was added ethyl 2-cyanoacetimidate hydrochloride (3.7 g) under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hour and then at room temperature for 2 hours. The precipitated was filtered off and the filtrate was concentrated under reduced pressure on a water bath to remove the excess ammonia. The residue was used as it was in the next reaction.

REFERENCE EXAMPLE 3 3-Amino-3-morpholinoacrylonitrile

In anhydrous ethanol (10 ml) was dissolved ethyl 2-cyanoacetimidate (1.0 g), followed by addition of morpholine (0.78 g). The mixture was stirred at room temperature for 4 hours, and the separated crystals were collected by filtration. This crystal crop was used as it was in the next reaction.

REFERENCE EXAMPLE 4 Carbamoylacetamidine

The title compound was synthesized by the known process (J. Amer. Chem. Soc., 73, 2760, 1951).

REFERENCE EXAMPLE 5 1-(2-Fluorophenyl)-1-acetamido-2-propanone

A mixture of 2-fluorophenylglycine (5.0 g), pyridine (15.6 g), and acetic anhydride (25.7 g) was heated at 140-150° C. for 4 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with diethyl ether. The ether layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate. The ether layer was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate) to provide the title compound as yellow oily substance (4.7 g).

The following compounds were synthesized in the similar manner as described in Reference Example 5.

1-Phenyl-1-acetamido-2-propanone,

1-(4-Fluorophenyl)-1-acetamido-2-propanone,

3-Acetamido-2-butanone,

1-(3-Nitrophenyl)-1-acetamido-2-propanone,

4-Phenyl-3-acetamido-2-butanone,

1-Phenyl-1-propanamido-2-butanone,

4-(4-Hydroxyphenyl)-3-acetamido-2-butanone,

1-Phenyl-1-isobutanamido-3-methyl-2-butanone,

2-Propanamido-3-pentanone,

4-(Indol-3-yl)-3-acetamido-2-butanone,

1-(3-Chlorophenyl)-1-acetamido-2-propanone,

1-Phenyl-1-butanamido-2-pentanone,

3-Acetamido-2-pentanone,

4-(4-Chlorophenyl)-3-acetamido-2-butanone,

1-(3-Pyridyl)-1-acetamido-2-propanone,

1-(2,5-Dichlorophenyl)-1-acetamido-2-propanone,

1-(2-Pyridyl)-1-acetamido-2-propanone,

1-(2-Naphthyl)-1-acetamido-2-propanone,

1-(4-Methoxyphenyl)-1-acetamido-2-propanone.

REFERENCE EXAMPLE 6 1,1-Dicyano-2-phenyl-2-(1-bromoethyl)ethylene

Propiophenone (30 g) and malononitrile (15 g) were added to benzene (100 ml), followed by addition of acetic acid (5.45 g) and ammonium acetate (1.8 g), the mixture was refluxed for 8 hours, while the byproduct water was continuously distilled off. After cooling to room temperature, the reaction mixture was washed with water, dried over MgSO₄, and concentrated under reduced pressure. The residual back oily substance was subjected to vacuum distillation to provide a pale yellow oily substance (32.5 g) (b.p. 120-125° C./2-3 mmHg).

The obtained compound (3.6 g) was dissolved in anhydrous benzene (30 ml), followed by addition of N-bromosuccinimide (3.6 g) and benzoyl peroxide (a catalyst amount), and the mixture was refluxed for 14 hours. After cooling to room temperature, the reaction mixture was filtered to remove insoluble matter and the filtrate was distilled under reduced pressure to remove the solvent. The residual tan oily substance was recrystallized from ethanol to provide the title compound as light-yellow crystals (2.99 g).

REFERENCE EXAMPLE 7 Sodium cyanoacetone enolate

A solution of 5-methylisoxazole (16.6 g) in ethanol was added dropwise to a solution of sodium ethoxide in ethanol (prepared from 4.6 g of sodium metal and 150 ml of ethanol) under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. Then, ether (150 ml) was added thereto and the mixture was further stirred for several minutes under ice-cooling. The sodium salt was then collected by filtration, washed with ether, and dried in vacuo to provide the title compound as white powder (18.1 g).

REFERENCE EXAMPLE 8 2-Acetyl-3-(2-fluorobenzoyl)butyronitrile

To a solution of 2-bromo-2'-fluoropropiophenone (3.45 g) in ethanol (40 ml) was added a solution of sodium cyanoacetone enolate (1.57 g), as obtained in Reference Example 7, in ethanol (15 ml) dropwise under ice-cooling and the mixture was stirred for 18 hours. The solvent was then distilled off under reduce pressure and the resulting residue was dissolved in ethyl acetate. This solution was washed with water and dried over MgSO₄, and the solvent was distilled off under reduced pressure. The resulting residual oily substance was purified by silica gel column chromatography [Wakogel C-200, 110 g; eluent: ethyl acetate/n-hexane (4:1)] to provide the title compound as yellow oily substance (1.43 g).

The following compounds were synthesized in the similar manner as described in Reference Example 8.

2-Acetyl-3-benzoylbutyronitrile

2-Acetyl-3-(3-isopropoxybenzoyl)propionitrile,

2-Acetyl-3-(4-trifluoromethoxybenzoyl)propionitrile,

2-Acetyl-3-(3-trifluoromethylbenzoyl)propionitrile,

2-Acetyl-3-(3-trifluoromethoxybenzoyl)propionitrile,

2-Acetyl-3-[4-(2-methoxy)ethoxybenzoyl]propionitrile,

2-Acetyl-3-(2-fluorobenzoyl)propionitrile,

2-Acetyl-3-(benzofuran-2-carbonyl)propionitrile,

2-Acetyl-3-(3,4-methylenedioxybenzoyl)propionitrile,

2-Acetyl-3-(2,5-difluorobenzoyl)propionitrile,

2-Acetyl-3-(4-chloro-3-methylbenzoyl)propionitrile,

2-Acetyl-3-(2-naphthoyl)propionitrile,

2-Acetyl-3-(3-bromobenzoyl)propionitrile,

2-Acetyl-3-(3-chloro-4-methylbenzoyl)butyronitrile,

2-Acetyl-3-(4-fluorobenzoyl)propionitrile,

2-Acetyl-3-(4-methanesulfonylaminobenzoyl)propionitrile,

2-Acetyl-3-(2-furoyl)butyronitrile,

2-Acetyl-3-(3-chlorobenzoyl)butyronitrile,

2-Acetyl-3-(3-methoxybenzoyl)propionitrile.

EXAMPLE 1 2-Amino-3-cyano-4-methyl-5-(2,5-difluorophenyl)pyrrole (compound No. 63)

To an ethanolic solution of 2-cyanoacetamidine obtained from ethyl 2-cyanoacetimidate hydrochloride (3.7 g) as in Reference Example 2, was added a solution of 2-bromo-2',5'-difluoropropiophenone (3.7 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was further stirred at room temperature overnight. This reaction mixture was poured into iced water and the separated crystal crop was collected by filtration. This crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: chloroform) and recrystallized from benzene-n-hexane to provide the title compound as yellow powder (0.58 g). m.p. 146-147° C.

Elemental analysis (C₁₂ H₉ F₂ N₃) Calcd. (%): C, 61.80; H, 3.89; N, 18.02 Found (%): C, 61.71; H, 3.91; N, 17.69

EXAMPLE 2 3-Cyano-5-(4-fluorophenyl)-4-methyl-2-morpholinopyrrole (compound No. 72)

In anhydrous ethanol (10 ml) was dissolved 3-amino-3-morpholinoacrylonitrile, as prepared from ethyl 2-cyano-acetimidate (1.0 g) and morpholine (0.78 g) as in Reference Example 3, followed by addition of sodium hydrogen carbonate (0.95 g). Then, a solution of 2-bromo-4'-fluoropropiophenone (2.06 g) in ethanol was added dropwise thereto at room temperature with stirring. The mixture was refluxed for 10 minutes and, then, stirred at room temperature overnight. The separated crystal crop was collected by filtration and recrystallized from ethanol to provide the title compound as colorless crystals (0.12 g). m.p. 245-247° C.

Elemental analysis (C₁₆ H₁₆ FN₃ O) Calcd. (%): C, 67.35; H, 5.65; N, 14.73 Found (%): C, 67.14; H, 5.86; N, 14.69

EXAMPLE 3 2-Amino-3-cyano-4H-[1]benzopyrano[4,3-b]pyrrole (compound No. 52)

To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C.

Elemental analysis (C₁₂ H₉ N₃ O) Calcd. (%): C, 68.24; H, 4.29; N, 19.89 Found (%): C, 68.29; H, 4.52; N, 19.81

EXAMPLE 4 2-Amino-3-carbamoyl-4-methyl-5-phenylpyrrole (compound No. 76)

To a solution (20 ml) of carbamoylacetamidine (5.1 g) in ethanol was added a solution of 2-bromopropiophenone (4.0 g) in ethanol dropwise thereto under ice-cooling with stirring and the mixture was then stirred at room temperature overnight. The insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained product was washed with benzene, purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 50% ethyl acetate/n-hexane), and recrystallized from ethyl acetate/diethyl ether to provide the title compound as colorless crystals (0.2 g). m.p. 195-197° C.

Elemental analysis (C₁₂ H₁₃ H₃ O) Calcd. (%): C, 66.96; H, 6.09; N, 19.52 Found (%): C, 66.95; H, 6.23; N, 19.38

EXAMPLE 5-(1) 2-amino-3-cyano-4-methyl-5-(2-fluorophenyl)pyrrole (compound No. 1)

1-(2-Fluorophenyl)-1-acetamido-2-propanone (3.13 g) and malononitrile (1.49 g) were dissolved in methanol (15 ml) and the solution was stirred under ice-cooling. Then, 55% aqueous solution of potassium hydroxide was added to the above solution to adjust to pH 10. The reaction mixture was then warmed and stirred at 55-60° C. for 0.5 hour. After cooling, the reaction mixture was poured into iced water and the resulting crystals were collected by filtration. This crude crystalline product was recrystallized from methanol-water and, further, from benzene to provide the title compound as colorless crystals (0.72 g). m.p. 117-118° C.

Elemental analysis (C₁₂ H₁₀ FN₃) Calcd. (%): C, 66.97; H, 4.68; N, 19.52 Found (%): C, 67.09; H, 4.74; N, 19.40

EXAMPLE 5-(2) 2-Amino-3-cyano-4-methyl-5-(2-fluorophenyl)pyrrole (compound No. 1; an alternative process)

To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2'- fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). the physical constants of this product were in agreement with those of the product obtained in Example 5-(1).

EXAMPLE 6 2-Amino-3-cyano-1-methoxycarbonylamino-4-methyl-5-phenylpyrrole (compound No. 13)

In anhydrous ethanol (30 ml) was suspended 1,1-dicyano-2-phenyl-2-(1-bromoethyl)ethylene (1.3 g) and while the suspension was stirred at 65° C., 10 ml of a suspension of methyl hydrazinecarboxylate (1.3 g) in anhydrous ethanol was added dropwise over about 5 minutes. The mixture was stirred at the same temperature for 4.5 hours and poured in iced water (200 g), and the resulting crystals were collected by filtration. The resulting crystals (1.0 g) were purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 30% ethyl acetate/n-hexane) and recrystallized from ethyl acetate/isopropyl ether to provide the title compound as colorless needles (0.48 g). m.p. 178-179° C.

Elemental analysis (C₁₄ H₁₄ N₄ O₂) Calcd. (%): C, 62.21; H, 5.22; N, 20.73 Found (%): C, 62.25; H, 4.92; N, 20.72

EXAMPLE 7 3-Cyano-4-methyl-2-methylamino-5-phenylpyrrole (compound No. 75)

2-Amino-3-cyano-4-methyl-5-phenylpyrrole (compound No. R1) (3.0 g), prepared in the process described in the Literature (J. Prakt. Chem., 318, 663, 1976), and ethyl orthoformate (12 ml) were refluxed for 4.5 hours. After cooling the reaction mixture to room temperature, the crystals which had separated out were collected by filtration. This crystal crop was washed with benzene and then petroleum ether, air-dried, and purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: chloroform) to obtain the iminoether as light-green crystals (1.9 g). This iminoether (1.85 g) was dissolved in anhydrous methanol (37 ml) and while the solution was stirred under ice-cooling, sodium borohydride (0.33 g) was added thereto in small portions. The mixture was stirred under cooling with water for 12 hours, after which the insoluble matter was removed by filtration and washed with benzene. The filtrate and washes were combined and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: chloroform) and recrystallized from benzene/n-hexane to provide the title compound as pale yellow crystals (0.37 g). m.p. 138-139° C.

Elemental analysis (C₁₃ H₁₃ N₃) Calcd. (%): C, 73.91; H, 6.20; N, 19.89 Found (%): C, 73.85; H, 6.52; N, 19.66

EXAMPLE 8 2-Benzylamino-3-cyano-4-methyl-5-(2-fluorophenyl)pyrrole (compound No. 74)

To a solution of 2-amino-3-cyano-4-methyl-5-(2fluorophenyl)pyrrole (Compound No. 1) obtained in Example 5 (0.21 g) in methylene chloride (5 ml) was added a small amount of magnesium sulfate and the mixture was stirred under ice-cooling. Then, a solution of benzaldehyde (0.11 g) in methylene chloride (5 ml) was added dropwise at the same temperature and the mixture was stirred at room temperature for 5 days. The magnesium sulfate was then filtered off and the filtrate was concentrated under reduced pressure. After the residue was dissolved in methanol (15 ml), sodium borohydride (76 mg) was added thereto under ice-cooling. This mixture was stirred at room temperature for 1 hour and the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the ethyl acetate layer was washed with water, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 50 g; eluent: chloroform/methanol=50/1) and the resulting crystals were recrystallized from benzene/n-hexane to provide the title compound as light-yellow powder (0.17 g). m.p. 151-152° C.

Elemental analysis (C₁₉ H₁₆ FN₃) Calcd. (%): C, 74.74; H, 5.28; N, 13.76 Found (%): C, 74.78; H, 5.38; N, 13.50

EXAMPLE 9 3-Cyano-4-methyl-2-(2-oxopyrrolidin-1-yl)-5-phenylpyrrole (compound No. 73)

To a solution of 3-cyano-4-methyl-2-amino-5-phenylpyrrole (4.9 g) in THF (80 ml) was added triethylamine (2.5 g) and while the mixture was stirred at -50° C., 4-chlorobutyryl chloride (3.5 g) was added. This reaction mixture was then stirred at room temperature for 1.5 hours, after which the insoluble matter was filtered off. The filtrate was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous solution of sodium hydrogen carbonate, dried over MgSO₄, and concentrated under reduced pressure. The residue was recrystallized from benzene/n-hexane. The crystals were suspended in ethanol (40 ml), and potassium tert-butoxide (1.32 g) was added thereto. The mixture was stirred at room temperature overnight and the resulting crystals were collected by filtration, washed with water, and air-dried. The crude crystals thus obtained were recrystallized from ethanol to provide the title compound as light-yellow needles (1.5 g). m.p. 140-141° C.

Elemental analysis (C₁₆ H₁₅ N₃ O) Calcd. (%): C, 72.43; H, 5.70; N, 15.84 Found (%): C, 72.42; H, 5.64; N, 15.79

EXAMPLE 10 2-Amino-3-cyano-4-methyl-5-(3-pyridyl)pyrrole hydrochloride (compound No. 14)

2-Amino-3-cyano-4-methyl-5-(3-pyridyl)pyrrole (compound No. 8) obtained in the same manner as Example 1 (5.0 g) was dissolved in methanol 220 ml) under heating, followed by addition of 40% HCl-methanol (4 ml) under ice-cooling with stirring. The separated crystals were collected by filtration, washed with methanol (50 ml) twice and diethyl ether (50 ml) 3 times, and air-dried. The crude crystals thus obtained were recrystallized from methanol to provide the title compound as reddish brown crystals (3.4 g). m.p. 279-281° C.

Elemental analysis (C₁₁ H₁₀ N₄.HCl) Calcd. (%): C, 56.30; H, 4.72; N, 23.89 Found (%): C, 56.08; H, 4.80; N, 23.90

EXAMPLE 11 5-(3-Chlorophenyl)-3-cyano-2-methylpyrrole (compound No. 84) and 2-(3-chlorophenyl)-3-cyano-5-methylpyrrole (compound No. 83)

N-(3-chlorobenzoyl)alanine (3.5 g) and 2-chloroacrylonitrile (13.3 g) were dissolved in acetic anhydride (100 ml) and the solution was stirred at 80° C. for 5 hours. This reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (Wakogel C-200, 600 g; eluent: methylene chloride) to fractionate the objective compounds. The compounds were respectively recrystallized from benzene/n-hexane.

Compound No. 84 was obtained as light-brown powder (291 mg). m.p. 208-209° C.

Elemental analysis (C₁₂ H₉ ClN₂) Calcd. (%): C, 66.52; H, 4.19; N, 12.93 Found (%): C, 66.47; H, 4.21; N, 12.87

Compound No. 83 was obtained as colorless scales (426 mg). m.p. 189-190° C.

Elemental analysis (C₁₂ H₉ ClN₂) Calcd. (%): C, 66.52; H, 4.19; N, 12.93 Found (%): C, 66.51; H, 4.24; N, 12.86

EXAMPLE 12 5-(2-Fluorophenyl)-3-cyano-2,4-dimethylpyrrole (compound No. 194)

To a solution of 2-acetyl-3-(2-fluorobenzoyl)butyronitrile (1.4 g) obtained in Reference Example 8 in acetic acid (15 ml) was added ammonium acetate (6.0 g) and the mixture was stirred at 90° C. for 15 minutes. This reaction mixture was poured in iced water and the resulting crystals were collected by filtration. This crystal crop was dissolved in benzene and dried over MgSO₄ and the solvent was distilled off under reduced pressure. The residual orange-colored crystals were purified by silica gel column chromatography (Wakogel C-200, 120 g; eluent: chloroform) and the resulting orange-colored powder was recrystallized from benzene/n-hexane to provide the title compound as colorless needles (0.36 g) m.p. 125-127° C.

Elemental analysis (C₁₃ H₁₁ FN₂) Calcd. (%): C, 72.88; H, 5.18; N, 13.08 Found (%): C, 73.11; H, 5.39; N, 13.08

The structural formulas and physicochemeical properties of the compounds synthesized in Examples 1-12 and the compounds synthesized in the similar procedures as the Examples (compound Nos. 2-12, 15-51, 53-62, 64-71, 77-82, 85-193, 195-266) are listed in Table 2. However, the present invention is by no means limited to those compounds.

In the column "Synthetic process" of the table, synthetic processes used for the production of the respective compounds are indicated as "A"-"I". "A and B", for instance, in the column means that the same compound was synthesized by both synthetic process A and synthetic process B.

                                      TABLE 2                                      __________________________________________________________________________                                                Molecular formula                        Elemental analysis                                                          Compound  m.p. (° C.) Calcd. (%) Synthetic                              No. Structural formula State Found (%) process                               __________________________________________________________________________        1                                                                                                                                     117-118                                                                      Colorless                                                                      crystals C.sub.12                                                              H.sub.10 FN.sub.3                                                               C, 66.97; H,                                                                  4.68; N, 19.52;                                                                C, 67.09; H,                                                                   4.74; N, 19.40; A                                                               and  B                   -  2                                                                                                                                  203-204                                                                      Greenish brown                                                                 needles C.sub.12                                                               H.sub.10 FN.sub.3.                                                             2/5H.sub.2 O  C,                                                               55.35; H, 4.58;                                                                N, 8.60;  C,                                                                   55.26; H, 4.67;                                                                N, 8.45; A                                                                       -  3                                                                           195-196  Brown                                                               needles C.sub.12                                                               H.sub.10 N.sub.4                                                               O.sub.2.1/10H.sub.                                                             2 O  C, 59.06; H,                                                              4.21; N, 22.96;                                                                C, 59.05; H,                                                                   4.26; N, 22.56; A         -  4                                                                                                                                  131-132                                                                      Light-brown                                                                    powder C.sub.13                                                                H.sub.13 N.sub.3                                                               C, 73.91; H,                                                                   6.20; N, 19.89;                                                                C, 74.10; H,                                                                   6.41; N, 19.62; A         -  5                                                                                                                                  104-105                                                                      Light-brown                                                                    powder C.sub.14                                                                H.sub.15 N.sub.3                                                               C, 74.64; H,                                                                   6.71; N, 18.65;                                                                C, 74.75; H,                                                                   6.89; N, 18.30; B         -  6                                                                                                                                  205-206                                                                      Light-brown                                                                    powder C.sub.12                                                                H.sub.10 ClN.sub.3                                                               C, 62.21; H,                                                                 4.35; N, 18.14;                                                                C, 62.07; H,                                                                   4.50; N, 18.00; B         -  7                                                                                                                                  129-130                                                                      Light-yellow                                                                   scales C.sub.14                                                                H.sub.15 N.sub.3                                                               C, 74.64; H,                                                                   6.71; N, 18.65;                                                                C, 74.52; H,                                                                   6.66; N, 18.63; B         -  8                                                                                                                                  228-230  Yellow                                                              powder C.sub.11                                                                H.sub.10 N.sub.4                                                               C, 66.65; H,                                                                   5.09; N, 28.26;                                                                C, 66.44; H,                                                                   5.07; N, 27.95; A         -  9                                                                                                                                  155-156                                                                      Colorless  prisms                                                              C.sub.12 H.sub.9                                                               Cl.sub.2 N.sub.3.H                                                             .sub.2 O  C,                                                                   52.39; H, 3.66;                                                                N, 15.27;  C,                                                                  52.50; H, 3.80;                                                                N, 14.84; A                                                                      -  10                                                                          213-214  Yellow                                                              scales C.sub.11                                                                H.sub.10 N.sub.4                                                               C, 66.65; H,                                                                   5.09; N, 28.26;                                                                C, 66.46; H,                                                                   5.14; N, 28.18; A         -  11                                                                                                                                 203-205                                                                      Yellowish  green                                                               powder C.sub.16                                                                H.sub.13 N.sub.3                                                               C, 77.71; H,                                                                   5.30; N, 16.99;                                                                C, 77.46; H,                                                                   5.30; N, 16.74; A         -  12                                                                                                                                 188-189  Light                                                               yellow  needles                                                                C.sub.13 H.sub.13                                                              N.sub.3 O  C,                                                                  68.70; H, 5.77;                                                                N, 18.49;  C,                                                                  68.84; H, 5.73;                                                                N, 18.65; A                                                                      -  13                                                                          178-179                                                                      Colorless                                                                      needles C.sub.14                                                               H.sub.14 N.sub.4                                                               O.sub.2  C,                                                                    62.21; H, 5.22;                                                                N, 20.73;  C,                                                                  62.25; H, 4.96;                                                                N, 20.72; D                                                                      -  14                                                                          279-281                                                                      Reddish brown                                                                  crystals C.sub.11                                                              H.sub.10 N.sub.4.H                                                             Cl  C, 56.30; H,                                                               4.72; N, 23.89;                                                                C, 56.08; H,                                                                   4.80; N, 23.90; A         -  15                                                                                                                                 190-191                                                                      Light-purple                                                                   crystals C.sub.11                                                              H.sub.9 N.sub.3                                                                C, 72.11; H,                                                                   4.95; N, 22.94;                                                                C, 72.41; H,                                                                   5.12; N, 22.87; A         -  16                                                                                                                                 247-248  Gray                                                                prisms C.sub.11                                                                H.sub.8 ClN.sub.3                                                               C, 60.70; H,                                                                  3.70; N, 19.31;                                                                C, 60.73; H,                                                                   3.85; N, 19.64; A         -  17                                                                                                                                 216-220                                                                      Light-brown                                                                    crystals C.sub.12                                                              H.sub.11 N.sub.3                                                               O.1/20H.sub.2 O                                                                C, 67.31; H,                                                                   5.22; N, 19.62;                                                                C, 67.58; H,                                                                   5.14; N, 19.30; A         -  18                                                                                                                                 221-224                                                                      silver-colored                                                                 crystals C.sub.12                                                              H.sub.11 N.sub.3                                                               C, 73.07; H,                                                                   5.62; N, 21.30;                                                                C, 73.00; H,                                                                   5.61; N, 21.20; A         -  19                                                                                                                                 159-160                                                                      Grayish green                                                                  crystals C.sub.12                                                              H.sub.11 N.sub.3                                                               O  C, 67.59; H,                                                                5.20; N, 19.71;                                                                C, 67.64; H,                                                                   5.23; N, 19.50; A         -  20                                                                                                                                 153-155                                                                      Grayish brown                                                                  crystals C.sub.12                                                              H.sub.11 N.sub.3                                                               O  C, 67.59; H,                                                                5.20; N, 19.71;                                                                C, 67.47; H,                                                                   5.30; N, 19.44; A         -  21                                                                                                                                 117-118                                                                      Light-green                                                                    crystals C.sub.10                                                              H.sub.9 N.sub.3 S                                                               C, 59.09; H,                                                                  4.46; N, 20.67;                                                                C, 59.26; H,                                                                   4.48; N, 20.76; A         -  22                                                                                                                                 166-167                                                                      Light-brown                                                                    crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               O  C, 69.69; H,                                                                6.27; N, 17.41;                                                                C, 69.95; H,                                                                   6.25; N, 17.51; A         -  23                                                                                                                                 218-219                                                                      Light-brown                                                                    crystals C.sub.12                                                              H.sub.9 Cl.sub.2                                                               N.sub.3  C,                                                                    54.16; H, 3.41;                                                                N, 15.79;  C,                                                                  53.82; H, 3.41;                                                                N, 15.78; A                                                                      -  24                                                                          212-213  Pale                                                                purple  crystals                                                               C.sub.12 H.sub.10                                                              ClN.sub.3  C,                                                                  62.21; H, 4.35;                                                                N, 18.14;  C,                                                                  62.39; H, 4.43;                                                                N, 18.24; A                                                                      -  25                                                                          206-209                                                                      Light-purple                                                                   cystals C.sub.12                                                               H.sub.10 BrN.sub.3                                                               C, 52.19; H,                                                                 3.65; N, 15.22;                                                                C, 52.07; H,                                                                   3.68; N, 15.17; A         -  26                                                                                                                                 160-161                                                                      Colorless                                                                      crystals C.sub.19                                                              H.sub.17 N.sub.3                                                               O  C, 75.23; H,                                                                5.65; N, 13.85;                                                                C, 75.06; H,                                                                   5.75; N, 13.80; A         -  27                                                                                                                                 113-115  Gray                                                                crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               O.sub.2  C,                                                                    65.36; H, 5.88;                                                                N, 16.33;  C,                                                                  65.17; H, 5.92;                                                                N, 16.38; A                                                                      -  28                                                                          216-218  Pale                                                                pink  crystals                                                                 C.sub.12 H.sub.10                                                              BrN.sub.3  C,                                                                  52.19; H, 3.65;                                                                N, 15.22;  C,                                                                  52.23; H, 3.75;                                                                N, 15.28; A                                                                      -  29                                                                          180-181  Green                                                               crystals C.sub.16                                                              H.sub.18 BrN.sub.3                                                              O.sub.2  C,                                                                   52.76; H, 4.98;                                                                N, 11.54;  C,                                                                  52.62; H, 5.01;                                                                N, 11.32; A                                                                      -  30                                                                          114-117                                                                      Light-yellow                                                                   crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               O  C, 69.69; H,                                                                6.27; N, 17.41;                                                                C, 69.86; H,                                                                   6.27; N, 17.37; A         -  31                                                                                                                                 198-200  Gray                                                                crystals C.sub.13                                                              H.sub.11 N.sub.3                                                               O.sub.2  C,                                                                    64.72; H, 4.60;                                                                N, 17.42;  C,                                                                  64.76; H, 4.76;                                                                N, 17.44; A                                                                      -  32                                                                          118-119                                                                      Colorless                                                                      crystals C.sub.15                                                              H.sub.17 N.sub.3                                                               O  C, 70.56; H,                                                                6.71; N, 16.46;                                                                C, 70.82; H,                                                                   6.77; N, 16.60; A         -  33                                                                                                                                 234-237                                                                      Light-green                                                                    cystals C.sub.13                                                               H.sub.13 N.sub.3                                                               O  C, 68.70; H,                                                                5.77; N, 18.49;                                                                C, 68.67; H,                                                                   5.94; N, 18.50; A         -  34                                                                                                                                 157-158                                                                      Light-pink                                                                     crystals C.sub.12                                                              H.sub.9 Cl.sub.2                                                               N.sub.3  C,                                                                    54.16; H, 3.41;                                                                N, 15.79;  C,                                                                  54.34; H, 3.41;                                                                N, 15.98; A                                                                      -  35                                                                          138-140                                                                      Light-gray                                                                     crystals C.sub.13                                                              H.sub.12 ClN.sub.3                                                               C, 63.55; H,                                                                 4.92; N, 17.10;                                                                C, 63.58; H,                                                                   4.77; N, 17.06; A         -  36                                                                                                                                 158-159                                                                      Light-brown                                                                    crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               O  C, 68.70; H,                                                                5.77; N, 18.49;                                                                C, 68.87; H,                                                                   5.89; N, 18.50; A         -  37                                                                                                                                 177-180  Gray                                                                crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               O  C, 69.69; H,                                                                6.27; N, 17.41;                                                                C, 69.53; H,                                                                   6.39; N, 17.32; A         -  38                                                                                                                                 278-281  Pale                                                                brown  crystals                                                                C.sub.17 H.sub.13                                                              N.sub.3  C,                                                                    78.74; H, 5.05;                                                                N, 16.20;  C,                                                                  78.83; H, 5.25;                                                                N, 16.30; A                                                                      -  39                                                                          224-226                                                                      Light-brown                                                                    crystals C.sub.15                                                              H.sub.11 N.sub.3                                                               C, 77.23; H,                                                                   4.75; N, 18.01;                                                                C, 77.30; H,                                                                   4.96; N, 18.01; A         -  40                                                                                                                                 257-260                                                                      Light-brown                                                                    crystals C.sub.11                                                              H.sub.7 Cl.sub.2                                                               N.sub.3  C,                                                                    52.41; H, 2.80;                                                                N, 16.67;  C,                                                                  52.46; H, 2.98;                                                                N, 16.45; A                                                                      -  41                                                                          214-218                                                                      Light-purple                                                                   crystals C.sub.11                                                              H.sub.8 FN.sub.3                                                               C, 65.67; H,                                                                   4.01; N, 20.88;                                                                C, 66.03; H,                                                                   4.24; N, 20.95; A         -  42                                                                                                                                 230-231                                                                      Light-orange                                                                   crystals C.sub.14                                                              H.sub.9 F.sub.6                                                                N.sub.3  C,                                                                    50.46; H, 2.72;                                                                N, 12.61;  C,                                                                  50.71; H, 2.62;                                                                N, 12.56; A                                                                      -  43                                                                          155-156                                                                      Light-red                                                                      crystals C.sub.10                                                              H.sub.9 N.sub.3 O                                                               C, 64.16; H,                                                                  4.85; N, 22.45;                                                                C, 64.34; H,                                                                   5.11; N, 22.37; A         -  44                                                                                                                                 203-206                                                                      Light-purple                                                                   crystals C.sub.9                                                               H.sub.7 N.sub.3 S                                                               C, 57.12; H,                                                                  3.73; N, 22.21;                                                                C, 57.32; H,                                                                   3.84; N, 22.19; A         -  45                                                                                                                                 215-220                                                                      Yellowish  brown                                                               crystals C.sub.11                                                              H.sub.10 N.sub.4.1                                                             /2H.sub.2 O  C,                                                                63.75; H, 5.35;                                                                N, 27.04;  C,                                                                  63.75; H, 5.31;                                                                N, 26.74; A                                                                      -  46                                                                          241-244                                                                      Light-brown                                                                    crystals C.sub.10                                                              H.sub.8 N.sub.4                                                                C, 65.21; H,                                                                   4.38; N, 30.42;                                                                C, 65.38; H,                                                                   4.60; N, 30.56; A         -  47                                                                                                                                 ≧275                                                                  Orange-colored                                                                 crystals C.sub.10                                                              H.sub.8 N.sub.4.HC                                                             l  C, 54.43; H,                                                                4.11; N, 25.39;                                                                C, 54.31; H,                                                                   4.31; N, 25.41; A         -  48                                                                                                                                 180-181  Gray                                                                crystals C.sub.9                                                               H.sub.7 N.sub.3 S                                                               C, 57.12; H,                                                                  3.73; N, 22.21;                                                                C, 57.20; H,                                                                   3.78; N, 22.08; A         -  49                                                                                                                                 192-193  Brown                                                               crystals C.sub.11                                                              H.sub.8 ClN.sub.3                                                               C, 60.70; H,                                                                  3.70; N, 19.31;                                                                C, 60.88; H,                                                                   3.67; N, 19.34; A         -  50                                                                                                                                 235-239                                                                      Light-gray                                                                     crystals C.sub.12                                                              H.sub.9 N.sub.3                                                                O.sub.2  C,                                                                    63.43; H, 3.99;                                                                N, 18.49;  C,                                                                  63.52; H, 4.00;                                                                N, 18.47; A                                                                      -  51                                                                          234-237  Purple                                                               crystals                                                                      C.sub.12 H.sub.10                                                              ClN.sub.3  C,                                                                  62.21; H, 4.35;                                                                N, 18.14;  C,                                                                  62.18; H, 4.24;                                                                N, 18.17; A                                                                      -  52                                                                          216-217                                                                      Light-brown                                                                    prisms C.sub.12                                                                H.sub.9 N.sub.3 O                                                               C, 68.24; H,                                                                  4.29; N, 19.89;                                                                C, 68.29; H,                                                                   4.52; N, 19.81; A         -  53                                                                                                                                 215-217                                                                      Light-gray                                                                     crystals C.sub.11                                                              H.sub.7 F.sub.2                                                                N.sub.3  C,                                                                    60.28; H, 3.32;                                                                N, 19.17;  C,                                                                  60.71; H, 3.53;                                                                N, 19.31; A                                                                      -  54                                                                          222-224  Gray                                                                crystals C.sub.11                                                              H.sub.7 F.sub.2                                                                N.sub.3  C,                                                                    60.28; H, 3.22;                                                                N, 19.17;  C,                                                                  60.45; H, 3.15;                                                                N, 19.22; A                                                                      -  55                                                                          247-251  Pale                                                                brown  crystals                                                                C.sub.13 H.sub.9                                                               N.sub.3 O  C,                                                                  69.95; H, 4.06;                                                                N, 18.82;  C,                                                                  70.30; H, 4.04;                                                                N, 19.02; A                                                                      -  56                                                                          260-263  Purple                                                               crystals                                                                      C.sub.11 H.sub.8                                                               BrN.sub.3  C,                                                                  50.41; H, 3.08;                                                                N, 16.03;  C,                                                                  50.26; H, 3.04;                                                                N, 16.07; A                                                                      -  57                                                                          265-270                                                                      Light-brown                                                                    crystals C.sub.12                                                              H.sub.12 N.sub.4                                                               O.sub.2 S.1/5H.sub                                                             .2 O  C, 51.49;                                                                H, 4.47; N,                                                                    20.02;  C, 51.67;                                                              H, 4.44; N,                                                                    19.67; A                  -  58                                                                                                                                 189-191                                                                      Light-yellow                                                                   plates C.sub.11                                                                H.sub.8 FN.sub.3                                                               C, 65.67; H,                                                                   4.01; N, 20.88;                                                                C, 66.15; H,                                                                   4.14; N, 20.81; A         -  59                                                                                                                                 192-193  Gray                                                                crystals C.sub.11                                                              H.sub.8 FN.sub.3.1                                                             /25C.sub.6                                                                     H.sub.6  C,                                                                    66.07; H, 4.06;                                                                N, 20.57;  C,                                                                  66.38; H, 4.23;                                                                N, 21.01; A                                                                      -  60                                                                          183-184                                                                      Light-brown                                                                    needles C.sub.12                                                               H.sub.8 F.sub.3                                                                N.sub.3  C,                                                                    57.37; H, 3.21;                                                                N, 16.73;  C,                                                                  57.40; H, 3.14;                                                                N, 16.86; A                                                                      -  61                                                                          160-161                                                                      Colorless  prisms                                                              C.sub.12 H.sub.10                                                              ClN.sub.3  C,                                                                  62.21; H, 4.35;                                                                N, 18.14;  C,                                                                  62.29; H, 4.38;                                                                N, 18.55; A                                                                      -  62                                                                          108-109                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.13 N.sub.3                                                               O.1/5H.sub.2 O                                                                 C, 67.63; H,                                                                   5.85; N, 18.20;                                                                C, 67.79; H,                                                                   5.79; N, 18.22; A         -  63                                                                                                                                 146-147  Yellow                                                              powder C.sub.12                                                                H.sub.9 F.sub.2                                                                N.sub.3  C,                                                                    61.80; H, 3.89;                                                                N, 18.02;  C,                                                                  61.71; H, 3.91;                                                                N, 17.69; A                                                                      -  64                                                                          127-128  Pale                                                                pink  needles                                                                  C.sub.13 H.sub.13                                                              N.sub.3  C,                                                                    73.91; H, 6.20;                                                                N, 19.89;  C,                                                                  73.84; H, 6.28;                                                                N, 19.76; A                                                                      -  65                                                                          181-182  Yellow                                                              powder C.sub.12                                                                H.sub.9 F.sub.2                                                                N.sub.3  C,                                                                    61.80; H, 3.89;                                                                N, 18.02;  C,                                                                  61.93; H, 3.98;                                                                N, 18.09; A                                                                      -  66                                                                          177-178                                                                      Light-brown                                                                    needles C.sub.13                                                               H.sub.10 F.sub.3                                                               N.sub.3  C,                                                                    58.87; H, 3.80;                                                                N, 15.84;  C,                                                                  58.88; H, 3.88;                                                                N, 15.96; A                                                                      -  67                                                                          202-203                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.10 F.sub.3                                                               N.sub.3  C,                                                                    58.87; H, 3.80;                                                                N, 15.84;  C,                                                                  58.58; H, 3.82;                                                                N, 15.73; A                                                                      -  68                                                                          223-225                                                                      Greenish brown                                                                 needles C.sub.14                                                               H.sub.13 N.sub.3                                                               O.sub.2  C,                                                                    65.87; H, 5.13;                                                                N, 16.46;  C,                                                                  65.76; H, 5.19;                                                                N, 16.30; A                                                                      -  69                                                                          143-144                                                                      Colorless                                                                      crystals C.sub.13                                                              H.sub.12 FN.sub.3                                                              O  C, 63.67; H,                                                                4.93; N, 17.13;                                                                C, 63.66; H,                                                                   4.92; N, 16.84; A         -  70                                                                                                                                 270-272  Yellow                                                               crystals                                                                      C.sub.17 H.sub.19                                                              N.sub.3  C,                                                                    76.95; H, 7.22;                                                                N, 15.84;  C,                                                                  76.87; H, 7.22;                                                                N, 15.95; A                                                                      -  71                                                                          253-260                                                                      Light-blue                                                                     crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               C, 76.46; H,                                                                   6.82; N, 16.72;                                                                C, 76.41; H,                                                                   6.61; N, 16.71; A         -  72                                                                                                                                 245-247                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.16 FN.sub.3                                                              O  C, 67.35; H,                                                                5.65; N, 14.73;                                                                C, 67.14; H,                                                                   5.86; N, 14.69; A         -  73                                                                                                                                 140-141                                                                      Light-yellow                                                                   needles C.sub.16                                                               H.sub.15 N.sub.3                                                               O  C, 72.43; H,                                                                5.70; N, 15.84;                                                                C, 72.42; H,                                                                   5.64; N, 15.79; G         -  74                                                                                                                                 151-152                                                                      Light-yellow                                                                   powder C.sub.19                                                                H.sub.16 FN.sub.3                                                               C, 74.74; H,                                                                  5.28; N, 13.76;                                                                C, 74.78; H,                                                                   5.38; N, 13.50; F         -  75                                                                                                                                 138-139                                                                      Light-yellow                                                                   needles C.sub.13                                                               H.sub.13 N.sub.3                                                               C, 73.91; H,                                                                   6.20; N, 19.89;                                                                C, 73.85; H,                                                                   6.72; N, 19.66; F         -  76                                                                                                                                 195-197                                                                      Colorless                                                                      crystals C.sub.12                                                              H.sub.13 N.sub.3                                                               O  C, 66.96; H,                                                                6.09; N, 19.52;                                                                C, 66.95; H,                                                                   6.23; N, 19.38; A         -  77                                                                                                                                 247-248                                                                      Light-brown                                                                    needles C.sub.12                                                               H.sub.9 N.sub.3                                                                O.sub.2  C,                                                                    63.43; H, 3.99;                                                                N, 18.49;  C,                                                                  63.44; H, 3.89;                                                                N, 18.53; H                                                                      -  78                                                                          235-236                                                                      Orange-colored                                                                 needles C.sub.12                                                               H.sub.9 N.sub.3                                                                O.sub.2  C,                                                                    63.43; H, 3.99;                                                                N, 18.49;  C,                                                                  63.35; H, 3.96;                                                                N, 18.56; H                                                                      -  79                                                                          239-240  Yellow                                                              powder C.sub.17                                                                H.sub.11 N.sub.3                                                               O.sub.2  C,                                                                    70.58; H, 3.83;                                                                N, 14.53;  C,                                                                  70.70; H, 3.93;                                                                N, 14.50; H                                                                      -  80                                                                          220-221                                                                      Light-yellow                                                                   needles C.sub.12                                                               H.sub.9 N.sub.3                                                                O.sub.2  C,                                                                    63.43; H, 3.99;                                                                N, 18.49;  C,                                                                  63.46; H, 4.19;                                                                N, 18.17; H                                                                      -  81                                                                          260-262                                                                      Light-yellow                                                                   powder C.sub.12                                                                H.sub.9 N.sub.3                                                                O.sub.2  C,                                                                    63.43; H, 3.99;                                                                N, 18.49;  C,                                                                  63.27; H, 3.98;                                                                N, 18.26; H                                                                      -  82                                                                          163-164                                                                      Colorless  prisms                                                              C.sub.12 H.sub.11                                                              N.sub.3  C,                                                                    73.07; H, 5.62;                                                                N, 21.30;  C,                                                                  73.47; H, 5.61;                                                                N, 21.38; I                                                                      -  83                                                                          189-190                                                                      Colorless  scales                                                              C.sub.12 H.sub.9                                                               ClN.sub.2  C,                                                                  66.52; H, 4.19;                                                                N, 12.93;  C,                                                                  66.51; H, 4.24;                                                                N, 12.86; H                                                                      -  84                                                                          208-209                                                                      Light-brown                                                                    powder C.sub.12                                                                H.sub.9 ClN.sub.2                                                               C, 66.52; H,                                                                  4.19; N, 12.93;                                                                C, 66.47; H,                                                                   4.21; N, 12.87; H         -  85                                                                                                                                 160-161  White                                                               powder C.sub.10                                                                H.sub.8 N.sub.2                                                                S.1/5H.sub.2 O                                                                 C, 62.60; H,                                                                   4.31; N, 14.60;                                                                C, 62.63; H,                                                                   4.31; N, 14.64; H         -  86                                                                                                                                 185-186  White                                                               powder C.sub.13                                                                H.sub.12 N.sub.2                                                               C, 79.56; H,                                                                   6.16; N, 14.27;                                                                C, 79.45; H,                                                                   5.94; N, 14.34; H         -  87                                                                                                                                 170-173  White                                                               powder C.sub.13                                                                H.sub.12 N.sub.2                                                               C, 79.56; H,                                                                   6.16; N, 14.27;                                                                C, 79.31; H,                                                                   6.19; N, 14.33; H         -  88                                                                                                                                 252-253  White                                                               powder C.sub.13                                                                H.sub.9 N.sub.3                                                                C, 75.35; H,                                                                   4.38; N, 20.28;                                                                C, 75.27; H,                                                                   4.39; N, 20.13; H         -  89                                                                                                                                 270-271  White                                                               powder C.sub.12                                                                H.sub.8 Cl.sub.2                                                               N.sub.2  C,                                                                    57.40; H, 3.21;                                                                N, 11.16;  C,                                                                  57.15; H, 3.34;                                                                N, 11.05; H                                                                      -  90                                                                          275-276                                                                      Colorless                                                                      needles C.sub.12                                                               H.sub.8 Cl.sub.2                                                               N.sub.2  C,                                                                    57.40; H, 3.21;                                                                N, 11.16;  C,                                                                  57.36; H, 3.34;                                                                N, 11.24; H                                                                      -  91                                                                          213-214  White                                                               powder C.sub.12                                                                H.sub.9 FN.sub.2.1                                                             /4H.sub.2 O  C,                                                                70.40; H, 4.67;                                                                N, 13.68;  C,                                                                  70.60; H, 4.81;                                                                N, 13.88; H                                                                      -  92                                                                          117-118  White                                                               powder C.sub.14                                                                H.sub.14 N.sub.2                                                               C, 79.97; H,                                                                   6.71; N, 13.32;                                                                C, 80.13; H,                                                                   7.00; N, 13.32; H         -  93                                                                                                                                 176-177  White                                                               powder C.sub.14                                                                H.sub.14 N.sub.2                                                               C, 79.97; H,                                                                   6.71; N, 13.32;                                                                C, 80.14; H,                                                                   6.65; N, 13.32; H         -  94                                                                                                                                 167-168  White                                                               powder C.sub.13                                                                H.sub.11 ClN.sub.2                                                               C, 67.68; H,                                                                 4.81; N, 12.14;                                                                C, 67.56; H,                                                                   4.81; N, 12.12; H         -  95                                                                                                                                 138-139  White                                                               powder C.sub.13                                                                H.sub.11 ClN.sub.2                                                             .1/5H.sub.2 O  C,                                                              66.64; H, 4.90;                                                                N, 11.96;  C,                                                                  66.56; H, 4.72;                                                                N, 11.87; H                                                                      -  96                                                                          172-173  White                                                               powder C.sub.14                                                                H.sub.13 ClN.sub.2                                                               C, 68.71; H,                                                                 5.35; N, 11.45;                                                                C, 68.68; H,                                                                   5.62; N, 11.70; H         -  97                                                                                                                                 105-106  White                                                               powder C.sub.14                                                                H.sub.13 ClN.sub.2                                                               C, 68.71; H,                                                                 5.35; N, 11.45;                                                                C, 68.71; H,                                                                   5.54; N, 11.61; H         -  98                                                                                                                                 91-92  White                                                                 powder C.sub.15                                                                H.sub.15 ClN.sub.2                                                             .1/10H.sub.2 O                                                                 C, 69.15; H,                                                                   5.88; N, 10.75;                                                                C, 68.96; H,                                                                   6.09; N, 10.68; H         -  99                                                                                                                                 167-168                                                                      Light-yellow                                                                   powder C.sub.23                                                                H.sub.25 N.sub.3                                                               O  C, 76.85; H,                                                                7.01; N, 11.69;                                                                C, 76.60; H,                                                                   7.18; N, 11.68; F         - 100                                                                                                                                 180-182                                                                      Light-yellow                                                                   scales C.sub.19                                                                H.sub.17 N.sub.3                                                               C, 79.41; H,                                                                   5.96; N, 14.62;                                                                C, 80.00; H,                                                                   6.05; N, 14.43; F         - 101                                                                                                                                 144-146                                                                      Colorless                                                                      needles C.sub.17                                                               H.sub.15 N.sub.3                                                               O  C, 73.63; H,                                                                5.45; N, 15.15;                                                                C, 73.37; H,                                                                   5.39; N, 14.91; F         - 102                                                                                                                                 235-237                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               C, 76.46; H,                                                                   6.82; N, 16.72;                                                                C, 76.37; H,                                                                   6.82; N, 16.54; A         - 103                                                                                                                                 218-219                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O  C, 71.89; H,                                                                6.41; N, 15.72;                                                                C, 71.68; H,                                                                   6.12; N, 15.73; A         - 104                                                                                                                                 233-236                                                                      Light-yellow                                                                   crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O  C, 71.89; H,                                                                6.41; N, 15.72;                                                                C, 71.88 H, 6.40;                                                              N, 15.59; A                                                                      - 105                                                                          264-265                                                                      Light-blue                                                                     crystals C.sub.15                                                              H.sub.14 ClN.sub.3                                                             .1/10H.sub.2 O                                                                 C, 65.86; H,                                                                   5.23; N, 15.36;                                                                C, 65.62; H,                                                                   4.89; N, 15.26; A         - 106                                                                                                                                 191-192                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.71; H,                                                                   6.96; N, 15.09; A         - 107                                                                                                                                 256-258                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.16 ClN.sub.3                                                               C, 67.25; H,                                                                 5.64; N, 14.70;                                                                C, 67.14; H,                                                                   5.64; N, 14.78; A         - 108                                                                                                                                 260-262  Blue                                                                crystals C.sub.15                                                              H.sub.14 ClN.sub.3                                                              O  C, 62.61; H,                                                               4.90; N, 14.60;                                                                C, 62.33; H,                                                                   5.05; N, 14.71; A         - 109                                                                                                                                 226-228                                                                      Light-blue                                                                     crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O.sub.2  C,                                                                    67.83; H, 6.05;                                                                N, 14.83;  C,                                                                  67.79; H, 6.15;                                                                N, 14.66; A                                                                      - 110                                                                          227-228                                                                      Light-yellow                                                                   crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.39; H,                                                                   6.87; N, 14.86; A         - 111                                                                                                                                 225-228                                                                      Light-yellow                                                                   crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               C, 77.38; H,                                                                   7.58; N, 15.04;                                                                C, 77.08; H,                                                                   7.50; N, 15.03; A         - 112                                                                                                                                 271-273  Blue                                                                needles C.sub.15                                                               H.sub.14 BrN.sub.3                                                              O  C, 54.23; H,                                                               4.25; N, 12.65;                                                                C, 54.22; H,                                                                   4.45; N, 12.62; A         - 113                                                                                                                                 281-283                                                                      Reddish brown                                                                  needles C.sub.16                                                               H.sub.16 N.sub.4                                                               O.sub.2  C,                                                                    64.85; H, 5.44;                                                                N, 18.91;  C,                                                                  64.74; H, 5.52;                                                                N, 18.82; A                                                                      - 114                                                                          239-240  Blue                                                                plates C.sub.17                                                                H.sub.19 N.sub.3                                                               C, 76.95; H,                                                                   7.22; N, 15.84;                                                                C, 76.91; H,                                                                   7.05; N, 15.82; A         - 115                                                                                                                                 219-220                                                                      Light-blue                                                                     crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O  C, 71.89; H,                                                                6.41; N, 15.72;                                                                C, 71.81; H,                                                                   6.73; N, 15.70; A         - 116                                                                                                                                 ≧300                                                                  Reddish brown                                                                  needles C.sub.15                                                               H.sub.14 N.sub.4                                                               O.sub.3  C,                                                                    60.40; H, 4.73;                                                                N, 18.78;  C,                                                                  60.30; H, 5.01;                                                                N, 18.63; A                                                                      - 117                                                                          233-236                                                                      Light-pink                                                                     needles C.sub.17                                                               H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.55; H,                                                                   6.45; N, 14.88; A         - 118                                                                                                                                 194-195                                                                      Light-brown                                                                    crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.20; H,                                                                   7.49; N, 14.22; A         - 119                                                                                                                                 200-202                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O.sub.2  C,                                                                    68.67; H, 6.44;                                                                N, 14.13;  C,                                                                  68.49; H, 6.55;                                                                N, 14.05; A                                                                      - 120                                                                          163-164                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.19 N.sub.3                                                               C, 75.85; H,                                                                   7.56; N, 16.59;                                                                C, 75.60; H,                                                                   7.86; N, 16.48; A         - 121                                                                                                                                 181-182                                                                      Colorless                                                                      crystals C.sub.17                                                              H.sub.18 FN.sub.3                                                               C, 72.06; H,                                                                  6.40; N, 14.83;                                                                C, 72.03; H,                                                                   6.62; N, 14.85; A         - 122                                                                                                                                 112-114  White                                                               powder C.sub.16                                                                H.sub.18 FN.sub.3                                                               C, 70.83; H,                                                                  6.69; N, 15.49;                                                                C, 71.30; H,                                                                   6.46; N, 15.51; A         - 123                                                                                                                                 245-250                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.16 FN.sub.3                                                               C, 71.36; H,                                                                  5.99; N, 15.60;                                                                C, 71.32; H,                                                                   6.01; N, 15.64; A         - 124                                                                                                                                 145-146                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.18 FN.sub.3                                                               C, 70.83; H,                                                                  6.69; N, 15.49;                                                                C, 70.81; H,                                                                   6.50; N, 15.62; A         - 125                                                                                                                                 228-229                                                                      Colorless                                                                      crystals C.sub.17                                                              H.sub.18 FN.sub.3                                                               C, 72.06; H,                                                                  6.40; N, 14.83;                                                                C, 72.27; H,                                                                   6.48; N, 14.43; A         - 126                                                                                                                                 215-217                                                                      Light-brown                                                                    crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               S  C, 65.34; H,                                                                5.88; N, 16.33;                                                                C, 65.48; H,                                                                   6.14; N, 16.26; A         - 127                                                                                                                                 260-265                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.15 Cl.sub.2                                                              N.sub.3  C,                                                                    60.01; H, 4.72;                                                                N, 13.12;  C,                                                                  60.17; H, 4.93;                                                                N, 13.09; A                                                                      - 128                                                                          207-209                                                                      Colorless                                                                      crystals C.sub.17                                                              H.sub.17 Cl.sub.2                                                              N.sub.3  C,                                                                    61.09; H, 5.13;                                                                N, 12.57;  C,                                                                  61.06; H, 5.31;                                                                N, 12.53; A                                                                      - 129                                                                          220-226                                                                      Colorless                                                                      crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.00; H,                                                                   7.29; N, 14.41; A         - 130                                                                                                                                 207-212                                                                      Colorless                                                                      crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O  C, 73.76; H,                                                                7.49; N, 13.58;                                                                C, 73.70; H,                                                                   7.58; N, 13.52; A         - 131                                                                                                                                 270-272                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.16 ClN.sub.3                                                               C, 67.25; H,                                                                 5.64; N, 14.70;                                                                C, 67.27; H,                                                                   5.70; N, 14.61; A         - 132                                                                                                                                 250-252                                                                      Colorless                                                                      crystals C.sub.17                                                              H.sub.18 ClN.sub.3                                                               C, 68.11; H,                                                                 6.05; N, 14.02;                                                                C, 68.13; H, 6.22                                                              N, 13.78; A                                                                      - 133                                                                          243-245                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.16 BrN.sub.3                                                               C, 58.19; H,                                                                 4.88; N, 12.72;                                                                C, 58.05; H,                                                                   4.94; N, 12.89; A         - 134                                                                                                                                 249-253                                                                      Colorless                                                                      crystals C.sub.17                                                              H.sub.18 BrN.sub.3                                                               C, 59.31; H,                                                                 5.27; N, 12.21;                                                                C, 59.21; H,                                                                   5.37; N, 12.28; A         - 135                                                                                                                                 168-170                                                                      Colorless                                                                      crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O.sub.2  C,                                                                    69.43; H, 6.80;                                                                N, 13.49;  C,                                                                  69.42; H, 6.89;                                                                N, 13.63; A                                                                      - 136                                                                          176-178                                                                      Colorless                                                                      crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O.sub.2  C,                                                                    70.13; H, 7.12;                                                                N, 12.91;  C,                                                                  70.07; H, 7.32;                                                                N, 12.93; A                                                                      - 137                                                                          231-233                                                                      Light-yellow                                                                   crystals C.sub.16                                                              H.sub.16 ClN.sub.3                                                               C, 67.25; H,                                                                 5.64; N, 14.70;                                                                C, 67.41; H,                                                                   5.54; N, 14.83; A         - 138                                                                                                                                 246-248                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.16 BrN.sub.3                                                               C, 58.19; H,                                                                 4.88; N, 12.72;                                                                C, 58.08; H,                                                                   4.96; N, 12.76; A         - 139                                                                                                                                 219-220                                                                      Light-gray                                                                     crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.50; H,                                                                   6.86; N, 14.84; A         - 140                                                                                                                                 171-172                                                                      Colorless                                                                      crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.15; H,                                                                   7.00; N, 14.23; A         - 141                                                                                                                                 229-235                                                                      Light-brown                                                                    crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O  C, 73.76; H,                                                                7.49; N, 13.58;                                                                C, 73.55; H,                                                                   7.54; N, 13.45; A         - 142                                                                                                                                 242-246                                                                      Colorless                                                                      crystals C.sub.20                                                              H.sub.25 N.sub.3                                                               O  C, 74.27; H,                                                                7.79; N, 12.99;                                                                C, 74.09; H,                                                                   7.52; N, 12.96; A         - 143                                                                                                                                 245-252                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.17 N.sub.3                                                               O.sub.2  C,                                                                    69.14; H, 5.80;                                                                N, 14.23;  C,                                                                  69.24; H, 5.83;                                                                N, 14.36; A                                                                      - 144                                                                          192-195                                                                      Light-blue                                                                     crystals C.sub.18                                                              H.sub.19 N.sub.3                                                               O.sub.2  C,                                                                    69.88; H, 6.19;                                                                N, 13.58;  C,                                                                  69.81; H, 6.17;                                                                N, 13.71; A                                                                      - 145                                                                          246-247                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.15 Cl.sub.2                                                              N.sub.3  C,                                                                    60.01; H, 4.72;                                                                N, 13.12;  C,                                                                  60.03; H, 4.70;                                                                N, 13.13; A                                                                      - 146                                                                          167-168                                                                      Light-gray                                                                     needles C.sub.13                                                               H.sub.12 N.sub.2                                                               O  C, 73.56; H,                                                                5.70; N, 13.20;                                                                C, 73.69; H,                                                                   5.65; N, 13.14; I         - 147                                                                                                                                 215-217                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.17 Cl.sub.2                                                              N.sub.3  C,                                                                    61.09; H, 5.13;                                                                N, 12.57;  C,                                                                  61.01; H, 5.19;                                                                N, 12.54; A                                                                      - 148                                                                          224-229                                                                      Light-brown                                                                    crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               S  C, 64.17; H,                                                                5.39; N, 17.27;                                                                C, 64.16; H,                                                                   5.29; N, 17.31; A         - 149                                                                                                                                 205-207                                                                      Light-green                                                                    crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               S  C, 65.34; H,                                                                5.88; N, 16.33;                                                                C, 65.23; H,                                                                   5.93; N, 16.11; A         - 150                                                                                                                                 190-192                                                                      Light-brown                                                                    powder C.sub.13                                                                H.sub.11 ClN.sub.2                                                               C, 67.68; H,                                                                 4.81; N, 12.14;                                                                C, 67.78; H,                                                                   4.93; N, 12.21; I         - 151                                                                                                                                 184-185                                                                      Ocherous  needles                                                              C.sub.12 H.sub.11                                                              N.sub.3  C,                                                                    73.07; H, 5.62;                                                                N, 21.30;  C,                                                                  73.39; H, 5.52;                                                                N, 21.24; I                                                                      - 152                                                                          243-249                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.18 ClN.sub.3                                                               C, 68.11; H,                                                                 6.05; N, 14.02;                                                                C, 68.25; H,                                                                   6.14; N, 13.96; A         - 153                                                                                                                                 187-188                                                                      Colorless                                                                      needles C.sub.14                                                               H.sub.13 ClN.sub.2                                                               C, 68.71; H,                                                                 5.35; N, 11.45;                                                                C, 68.77; H,                                                                   5.46; N, 11.40; I         - 154                                                                                                                                 206-207                                                                      Colorless                                                                      crystals C.sub.18                                                              H.sub.20 ClN.sub.3                                                               C, 68.89; H,                                                                 6.42; N, 13.39;                                                                C, 68.78; H,                                                                   6.55; N, 13.41; A         - 155                                                                                                                                 210-213                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.39; H,                                                                   6.92; N, 14.83; A         - 156                                                                                                                                 199-201                                                                      Light-red                                                                      needles C.sub.13                                                               H.sub.11 FN.sub.2                                                               C, 72.88; H,                                                                  5.18; N, 13.08;                                                                C, 73.15; H,                                                                   5.04; N, 13.13; I         - 157                                                                                                                                 221-222                                                                      Light-yellow                                                                   crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               O.sub.2 S.1/10H.su                                                             b.2 O  C, 56.34;                                                               H, 4.80; N,                                                                    15.16;  C, 56.23;                                                              H, 4.62; N,                                                                    15.02; I                  - 158                                                                                                                                 140-142                                                                      Light-yellow                                                                   needles C.sub.11                                                               H.sub.10 N.sub.2                                                               O  C, 70.95; H,                                                                5.41; N, 15.04;                                                                C, 71.07; H,                                                                   5.70; N, 15.11; I         - 159                                                                                                                                 195-196                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.11 BrN.sub.2                                                               C, 56.75; H,                                                                 4.03; N, 10.18;                                                                C, 56.54; H,                                                                   4.06; N, 10.14; I         - 160                                                                                                                                 221-222                                                                      Light-yellow                                                                   needles C.sub.14                                                               H.sub.13 N.sub.3                                                               O.1/5H.sub.2 O                                                                 C, 69.23; H,                                                                   5.56; N, 17.30;                                                                C, 69.26; H,                                                                   5.58; N, 17.19; I         - 161                                                                                                                                 211-213                                                                      Light-brown                                                                    crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.07; H,                                                                   7.37; N, 14.16; A         - 162                                                                                                                                 203-204  Gray                                                                powder C.sub.16                                                                H.sub.12 N.sub.2                                                               C, 82.73; H,                                                                   5.21; N, 12.06;                                                                C, 82.91; H,                                                                   5.40; N, 12.03; I         - 163                                                                                                                                 200-202                                                                      Light-brown                                                                    crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.07; H,                                                                   7.33; N, 13.99; A         - 164                                                                                                                                 219-223                                                                      Light-brown                                                                    crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O.1/10H.sub.2 O                                                                C, 73.33; H,                                                                   7.77; N, 13.50;                                                                C, 73.17; H,                                                                   7.57; N, 13.28; A         - 165                                                                                                                                 297-301                                                                      Light-yellow                                                                   powder C.sub.17                                                                H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.17; H,                                                                   6.45; N, 14.92; A         - 166                                                                                                                                 140-141                                                                      Light-blue                                                                     crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O.1/10H.sub.2 O                                                                C, 72.75; H,                                                                   7.19; N, 14.14;                                                                C, 72.60; H,                                                                   7.18; N, 14.06; A         - 167                                                                                                                                 258-261                                                                      Light-yellow                                                                   crystals C.sub.19                                                              H.sub.17 N.sub.3.1                                                             /10H.sub.2 O  C,                                                               78.92; H, 6.00;                                                                N, 14.53;  C,                                                                  78.81; H, 6.23;                                                                N, 14.67; A                                                                      - 168                                                                          240-143  Brown                                                               crystals C.sub.20                                                              H.sub.19 N.sub.3.1                                                             /10H.sub.2 O  C,                                                               79.23; H, 6.38;                                                                N, 13.86;  C,                                                                  79.08; H, 6.59;                                                                N, 13.71; A                                                                      - 169                                                                          227-231  Brown                                                               crystals C.sub.21                                                              H.sub.19 N.sub.3                                                               C, 80.48; H,                                                                   6.11; N, 13.41;                                                                C, 80.23; H,                                                                   6.17; N, 13.45; A         - 170                                                                                                                                 257-260                                                                      Light-yellow                                                                   crystals C.sub.15                                                              H.sub.13 Cl.sub.2                                                              N.sub.3  C,                                                                    58.84; H, 4.28;                                                                N, 13.72;  C,                                                                  58.51; H, 4.25;                                                                N, 13.83; A                                                                      - 171                                                                          216-221                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.17 N.sub.3                                                               O.sub.2  C,                                                                    69.14; H, 5.80;                                                                N, 14.23;  C,                                                                  69.27; H, 5.68;                                                                N, 14.27; A                                                                      - 172                                                                          231-236                                                                      Light-brown                                                                    crystals C.sub.15                                                              H.sub.14 FN.sub.3                                                               C, 70.57; H,                                                                  5.53; N, 16.46;                                                                C, 70.56; H,                                                                   5.72; N, 16.63; A         - 173                                                                                                                                 203-204                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.16 FN.sub.3                                                               C, 71.36; H,                                                                  5.99; N, 15.60;                                                                C, 71.43; H,                                                                   6.17; N, 15.64; A         - 174                                                                                                                                 238-240  Gray                                                                powder C.sub.13                                                                H.sub.11 ClN.sub.2                                                               C, 67.68; H,                                                                 4.81; N, 12.14;                                                                C, 68.03; H,                                                                   4.84; N, 12.22; I         - 175                                                                                                                                 213-215  Gray                                                                powder C.sub.12                                                                H.sub.8 F.sub.2                                                                N.sub.2  C,                                                                    66.05; H, 3.70;                                                                N, 12.84;  C,                                                                  66.13; H, 3.65;                                                                N, 12.92; I                                                                      - 176                                                                          235-236                                                                      Light-gray                                                                     crystals C.sub.15                                                              H.sub.16 N.sub.4                                                               C, 71.40; H,                                                                   6.39; N, 22.21;                                                                C, 71.35; H,                                                                   6.43; N, 22.03; A         - 177                                                                                                                                 240-242  Brown                                                               powder C.sub.15                                                                H.sub.16 N.sub.4                                                               C, 71.40; H,                                                                   6.39; N, 22.21;                                                                C, 71.43; H,                                                                   6.49; N, 22.71; A         - 178                                                                                                                                 251-260                                                                      Light-brown                                                                    powder C.sub.14                                                                H.sub.14 N.sub.4                                                               C, 70.57; H,                                                                   5.92; N, 23.51;                                                                C, 70.19; H,                                                                   5.99; N, 23.11; A         - 179                                                                                                                                 248-251                                                                      Light-purple                                                                   crystals C.sub.14                                                              H.sub.14 N.sub.4                                                               C, 70.57; H,                                                                   5.92; N, 23.51;                                                                C, 70.58; H,                                                                   5.96; N, 23.52; A         - 180                                                                                                                                 270-276                                                                      Orange-colored                                                                 needles C.sub.14                                                               H.sub.14 N.sub.4.H                                                             Cl  C, 61.20; H,                                                               5.50; N, 20.39;                                                                C, 61.23; H,                                                                   5.60; N, 20.02; A         - 181                                                                                                                                 230-234  Brown                                                               crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               S.1/7H.sub.2 O                                                                 C, 63.50; H,                                                                   5.45; N, 17.08;                                                                C, 63.91; H,                                                                   5.51; N, 16.68; A         - 182                                                                                                                                 220-223  Brown                                                               crystals C.sub.15                                                              H.sub.14 ClN.sub.3                                                             .1/5H.sub.2 O  C,                                                              65.43; H, 5.27;                                                                N, 15.26;  C,                                                                  65.81; H, 5.15;                                                                N, 14.94; A                                                                      - 183                                                                          236-240                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.16 ClN.sub.3                                                               C, 67.25; H,                                                                 5.64; N, 14.70;                                                                C, 67.11; H,                                                                   5.69; N, 14.48; A         - 184                                                                                                                                 225-228                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.15 N.sub.3                                                               O.sub.2  C,                                                                    68.31; H, 5.37;                                                                N, 14.94;  C,                                                                  68.12; H, 5.40;                                                                N, 14.81; A                                                                      - 185                                                                          211-212  Gray                                                                powder C.sub.13                                                                H.sub.10 N.sub.2                                                               O.sub.2  C,                                                                    69.02; H, 4.46;                                                                N, 12.38;  C,                                                                  69.08; H, 4.55;                                                                N, 12.37; I                                                                      - 186                                                                          212-213                                                                      Colorless                                                                      crystals C.sub.15                                                              H.sub.13 F.sub.2                                                               N.sub.3  C,                                                                    65.93; H, 4.79;                                                                N, 15.38;  C,                                                                  65.93; H, 4.68;                                                                N, 15.16; A                                                                      - 187                                                                          206-207                                                                      Light-green                                                                    crystals C.sub.15                                                              H.sub.13 F.sub.2                                                               N.sub.3  C,                                                                    65.93; H, 4.79;                                                                N, 15.38;  C,                                                                  66.50; H, 4.92;                                                                N, 15.32; A                                                                      - 188                                                                          260-268                                                                      Light-yellow                                                                   needles C.sub.17                                                               H.sub.15 N.sub.3                                                               O  C, 73.63; H,                                                                5.45; N, 15.15;                                                                C, 73.68; H,                                                                   5.58; N, 15.14; A         - 189                                                                                                                                 208-209                                                                      Light-yellow                                                                   needles C.sub.14                                                               H.sub.10 N.sub.2                                                               O  C, 75.66; H,                                                                4.54; N, 12.60;                                                                C, 75.50; H,                                                                   4.78; N, 12.58; I         - 190                                                                                                                                 201-203                                                                      Reddish brown                                                                  powder C.sub.16                                                                H.sub.18 N.sub.4                                                               C, 72.15; H,                                                                   6.81; N, 21.04;                                                                C, 71.83; H,                                                                   6.98; N, 21.07; A         - 191                                                                                                                                 160-161                                                                      Light-yellow                                                                   crystals C.sub.16                                                              H.sub.18 N.sub.4                                                               C, 72.15; H,                                                                   6.81; N, 21.04;                                                                C, 72.11; H,                                                                   6.95; N, 20.93; A         - 192                                                                                                                                 190-191  Purple                                                               crystals                                                                      C.sub.10 H.sub.13                                                              N.sub.3  C,                                                                    68.54; H, 7.48;                                                                N, 23.98;  C,                                                                  68.55; H, 7.35;                                                                N, 24.09; A                                                                      - 193                                                                          189-191  Purple                                                               crystals                                                                      C.sub.11 H.sub.15                                                              N.sub.3  C,                                                                    69.81; H, 7.99;                                                                N, 22.20;  C,                                                                  69.64; H, 8.16;                                                                N, 21.92; A                                                                      - 194                                                                          125-127                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.11 FN.sub.2                                                               C, 72.88; H,                                                                  5.18; N, 13.08;                                                                C, 73.11; H,                                                                   5.39; N, 13.08; I         - 195                                                                                                                                 202-203  White                                                               powder C.sub.20                                                                H.sub.15 N.sub.3                                                               O  C, 76.66; H,                                                                4.83; N, 13.41;                                                                C, 76.94; H,                                                                   4.94; N, 13.37; I         - 196                                                                                                                                 196-198                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.18 N.sub.4                                                               C, 72.15; H,                                                                   6.81; N, 21.04;                                                                C, 72.03; H,                                                                   6.88; N, 21.39; A         - 197                                                                                                                                 156-158                                                                      Light-yellow                                                                   crystals C.sub.14                                                              H.sub.14 N.sub.4                                                               C, 70.57; H,                                                                   5.92; N, 23.51;                                                                C, 70.72; H,                                                                   6.04; N, 23.58; A         - 198                                                                                                                                 164-165  Purple                                                               crystals                                                                      C.sub.12 H.sub.17                                                              N.sub.3  C,                                                                    70.90; H, 8.43;                                                                N, 20.67;  C,                                                                  70.56; H, 8.56;                                                                N, 20.67; A                                                                      - 199                                                                          189-191                                                                      Light-brown                                                                    crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.13; H,                                                                   7.42; N, 14.27; A         - 200                                                                                                                                 204-206                                                                      Light-blue                                                                     crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O  C, 73.76; H,                                                                7.49; N, 13.58;                                                                C, 73.72; H,                                                                   7.73; N, 13.63; A         - 201                                                                                                                                 179-183                                                                      Light-green                                                                    crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O.sub.2  C,                                                                    69.43; H, 6.80;                                                                N, 13.49;  C,                                                                  69.48; H, 6.73;                                                                N, 13.56; A                                                                      - 202                                                                          179-180                                                                      Colorless                                                                      crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O.sub.2  C,                                                                    70.13; H, 7.12;                                                                N, 12.91;  C,                                                                  70.01; H, 7.06;                                                                N, 12.84; A                                                                      - 203                                                                          153-154                                                                      Light-brown                                                                    crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O.sub.2  C,                                                                    70.13; H, 7.12;                                                                N, 12.91;  C,                                                                  70.18; H, 7.15;                                                                N, 12.86; A                                                                      - 204                                                                          172-174                                                                      Colorless                                                                      crystals C.sub.20                                                              H.sub.25 N.sub.3                                                               O.sub.2  C,                                                                    70.77; H, 7.42;                                                                N, 12.38;  C,                                                                  70.63; H, 7.36;                                                                N, 12.38; A                                                                      - 205                                                                          211-213                                                                      Light-brown                                                                    crystals C.sub.22                                                              H.sub.21 N.sub.3                                                               O  C, 76.94; H,                                                                6.16; N, 12.24;                                                                C, 76.83; H,                                                                   6.30; N, 12.22; A         - 206                                                                                                                                 218-222                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.15 N.sub.3                                                               O.1/10H.sub.2 O                                                                C, 71.94; H,                                                                   5.73; N, 15.73;                                                                C, 72.02; H,                                                                   5.77; N, 15.64; A         - 207                                                                                                                                 178-179                                                                      Light-yellow                                                                   crystals C.sub.15                                                              H.sub.14 FN.sub.3                                                               C, 70.57; H,                                                                  5.53; N, 16.46;                                                                C, 70.65; H,                                                                   5.64; N, 16.44; A         - 208                                                                                                                                 165-166  Blue                                                                crystals C.sub.16                                                              H.sub.16 FN.sub.3                                                               C, 71.36; H,                                                                  5.99; N, 15.60;                                                                C, 71.38; H,                                                                   6.14; N, 15.57; A         - 209                                                                                                                                 220-221                                                                      Light-yellow                                                                   crystals C.sub.15                                                              H.sub.14 FN.sub.3                                                               C, 70.57; H,                                                                  5.53; N, 16.46;                                                                C, 70.54; H,                                                                   5.65; N, 16.42; A         - 210                                                                                                                                 182-183  Blue                                                                crystals C.sub.16                                                              H.sub.16 FN.sub.3                                                               C, 71.36; H,                                                                  5.99; N, 15.60;                                                                C, 71.56; H,                                                                   5.93; N, 15.65; A         - 211                                                                                                                                 229-234                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.17 N.sub.3                                                               O  C, 73.10; H,                                                                6.13; N, 15.04;                                                                C, 72.84; H,                                                                   6.12; N, 14.83; A         - 212                                                                                                                                 263-265  White                                                               powder C.sub.15                                                                H.sub.14 N.sub.4                                                               O  C, 67.65; H,                                                                5.30; N, 21.04;                                                                C, 67.62; H,                                                                   5.29; N, 20.82; A         - 213                                                                                                                                 171-172                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               C, 76.95; H,                                                                   7.22; N, 15.84;                                                                C, 76.87; H,                                                                   7.18; N, 15.74; A         - 214                                                                                                                                 118-119  Blue                                                                plates C.sub.16                                                                H.sub.19 N.sub.3                                                               C, 75.85; H,                                                                   7.56; N, 16.59;                                                                C, 76.08; H,                                                                   7.17; N, 16.57; A         - 215                                                                                                                                 238-239                                                                      Colorless                                                                      crystals C.sub.21                                                              H.sub.20 N.sub.4                                                               C, 76.80; H,                                                                   6.14; N, 17.06;                                                                C, 77.07; H,                                                                   6.27; N, 17.08; A         - 216                                                                                                                                 205-206                                                                      Light-yellow                                                                   crystals C.sub.17                                                              H.sub.18 N.sub.4                                                               O  C, 69.37; H,                                                                6.16; N, 19.03;                                                                C, 69.41; H,                                                                   6.52; N, 19.06; A         - 217                                                                                                                                 177-178                                                                      Colorless                                                                      crystals C.sub.20                                                              H.sub.19 N.sub.5                                                               C, 72.92; H,                                                                   5.81; N, 21.26;                                                                C, 73.23; H,                                                                   6.04; N, 21.21; A         - 218                                                                                                                                 163-164  Gray                                                                powder C.sub.15                                                                H.sub.16 N.sub.2                                                               O.sub.2  C,                                                                    70.29; H, 6.29;                                                                N, 10.93;  C,                                                                  70.19; H, 6.28;                                                                N, 10.95; I                                                                      - 219                                                                          172-173                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.9 F.sub.3                                                                N.sub.2 O  C,                                                                  58.65; H, 3.41;                                                                N, 10.52;  C,                                                                  58.88; H, 3.23;                                                                N, 10.63; I                                                                      - 220                                                                          201-202                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.9 F.sub.3                                                                N.sub.2  C,                                                                    62.40; H, 3.63;                                                                N, 11.20;  C,                                                                  62.37; H, 3.74;                                                                N, 11.23; I                                                                      - 221                                                                          190-192                                                                      Light-yellow                                                                   crystals C.sub.18                                                              H.sub.20 N.sub.4                                                               O  C, 70.11; H,                                                                6.54; N, 18.17;                                                                C, 70.88; H,                                                                   6.44; N, 18.14; A         - 222                                                                                                                                 215-216                                                                      Light-orange                                                                   crystals C.sub.21                                                              H.sub.21 N.sub.5                                                               C, 73.44; H,                                                                   6.16; N, 20.39;                                                                C, 73.95; H,                                                                   6.24; N, 20.34; A         - 223                                                                                                                                 259-263                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.14 F.sub.3                                                               N.sub.3  C,                                                                    62.95; H, 4.62;                                                                N, 13.76;  C,                                                                  63.01; H, 5.16;                                                                N, 13.73; A                                                                      - 224                                                                          207-208                                                                      Light-gray                                                                     crystals C.sub.17                                                              H.sub.16 F.sub.3                                                               N.sub.3  C,                                                                    63.94; H, 5.05;                                                                N, 13.16;  C,                                                                  64.61; H, 4.83;                                                                N, 13.08; A                                                                      - 225                                                                          232-233                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.16 F.sub.3                                                               N.sub.3 O  C,                                                                  60.89; H, 4.81;                                                                N, 12.53;  C,                                                                  60.88; H, 4.92;                                                                N, 12.29; A                                                                      - 226                                                                          252-260  Brown                                                               crystals C.sub.16                                                              H.sub.18 N.sub.4                                                               O.sub.2 S  C,                                                                  58.16; H, 5.49;                                                                N, 16.96;  C,                                                                  57.92; H, 5.46;                                                                N, 16.84; A                                                                      - 227                                                                          225-228                                                                      Light-yellow                                                                   crystals C.sub.16                                                              H.sub.14 F.sub.3                                                               N.sub.3 O  C,                                                                  59.81; H, 4.39;                                                                N, 13.08;  C,                                                                  60.06; H, 4.58;                                                                N, 13.08; A                                                                      - 228                                                                          198-200                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O  C, 71.89; H,                                                                6.41; N, 15.72                                                                 C, 72.02; H,                                                                   6.37; N, 15.77; A         - 229                                                                                                                                 172-174                                                                      Light-yellow                                                                   crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.60; H,                                                                   6.76; N, 14.51; A         - 230                                                                                                                                 210-216                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.18 N.sub.4                                                               O.sub.2 S  C,                                                                  58.16; H, 5.49;                                                                N, 16.96;  C,                                                                  58.06; H, 5.64;                                                                N, 16.82; A                                                                      - 231                                                                          274-281                                                                      Light-yellow                                                                   crystals C.sub.16                                                              H.sub.14 F.sub.3                                                               N.sub.3  C,                                                                    62.95; H, 4.62;                                                                N, 13.76;  C,                                                                  63.19; H, 4.61;                                                                N, 13.66; A                                                                      - 232                                                                          167-168                                                                      Colorless                                                                      needles C.sub.13                                                               H.sub.9 F.sub.3                                                                N.sub.2 O.1/10C.su                                                             b.6 H.sub.6  C,                                                                59.61; H, 3.53;                                                                N, 10.22;  C,                                                                  59.54; H, 3.27;                                                                N, 10.43; I                                                                      - 233                                                                          245-248  Gray                                                                crystals C.sub.17                                                              H.sub.20 N.sub.4                                                               O.sub.2 S.C.sub.2                                                              H.sub.5 OH  C,                                                                 58.44; H, 6.71;                                                                N, 14.35;  C,                                                                  58.26; H, 6.42;                                                                N, 14.58; A                                                                      - 234                                                                          216-217                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.14 F.sub.3                                                               N.sub.3  C,                                                                    62.95; H, 4.62;                                                                N, 13.76;  C,                                                                  63.16; H, 4.38;                                                                N, 13.76; A                                                                      - 235                                                                          273-278                                                                      Light-brown                                                                    powder C.sub.16                                                                H.sub.16 N.sub.4                                                               O.sub.2  C,                                                                    64.85; H, 5.44;                                                                N, 18.91;  C,                                                                  64.91; H, 5.22;                                                                N, 18.99; A                                                                      - 236                                                                          213-214                                                                      Light-blue                                                                     crystals C.sub.15                                                              H.sub.15 N.sub.3                                                               S  C, 66.88; H,                                                                5.61; N, 15.60;                                                                C, 66.81; H,                                                                   5.63; N, 15.54; A         - 237                                                                                                                                 252-253                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               OS  C, 64.19; H,                                                               5.72; N, 14.04;                                                                C, 64.18; H,                                                                   5.76; N, 14.08; A         - 238                                                                                                                                 155-157                                                                      Light-brown                                                                    powder C.sub.18                                                                H.sub.21 N.sub.3                                                               O.sub.2  C,                                                                    69.43; H, 6.80;                                                                N, 13.49;  C,                                                                  69.29; H, 6.67;                                                                N, 13.46; A                                                                      - 239                                                                          295-298                                                                      Light-brown                                                                    powder C.sub.18                                                                H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 72.94; H,                                                                   6.92; N, 13.92; A         - 240                                                                                                                                 163-164                                                                      Light-green                                                                    crystals C.sub.19                                                              H.sub.23 N.sub.3                                                               O  C, 73.76; H,                                                                7.49; N, 13.58;                                                                C, 73.80; H,                                                                   7.60; N, 13.58; A         - 241                                                                                                                                 196-199                                                                      Yellowish  green                                                               crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               O  C, 68.70; H,                                                                5.77; N, 18.49;                                                                C, 68.29; H,                                                                   5.55; N, 18.33; A         - 242                                                                                                                                 158-161                                                                      Deep-green                                                                     crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               O.3/10H.sub.2 O                                                                C, 68.16; H,                                                                   6.37; N, 17.03;                                                                C, 67.98; H,                                                                   5.97; N, 17.00; A         - 243                                                                                                                                 175-176                                                                      Light-brown                                                                    crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               C, 73.91; H,                                                                   6.20; N, 19.89;                                                                C, 73.81; H,                                                                   6.21; N, 19.77; A         - 244                                                                                                                                 238-245  White                                                               powder C.sub.16                                                                H.sub.16 FN.sub.3                                                              O  C, 67.35; H,                                                                5.65; N, 14.73;                                                                C, 67.42; H,                                                                   5.74; N, 14.53; A         - 245                                                                                                                                 211-212  Blue                                                                crystals C.sub.17                                                              H.sub.18 FN.sub.3                                                              O  C, 68.21; H,                                                                6.06; N, 14.04;                                                                C, 68.20; H,                                                                   6.21; N, 13.73; A         - 246                                                                                                                                 222-224                                                                      Light-brown                                                                    crystals C.sub.16                                                              H.sub.16 FN.sub.3                                                              O  C, 67.35; H,                                                                5.65; N, 14.73;                                                                C, 67.54; H,                                                                   5.88; N, 14.66; A         - 247                                                                                                                                 203-206                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.18 FN.sub.3                                                              O  C, 68.21; H,                                                                6.06; N, 14.04;                                                                C, 68.38; H,                                                                   6.11; N, 13.96; A         - 248                                                                                                                                 207-209                                                                      Light-brown                                                                    crystals C.sub.18                                                              H.sub.20 FN.sub.3                                                              O  C, 68.99; H,                                                                6.43; N, 13.41;                                                                C, 69.01; H,                                                                   6.39; N, 13.32; A         - 249                                                                                                                                 169-171                                                                      Light-yellow                                                                   crystals C.sub.17                                                              H.sub.18 FN.sub.3                                                              O  C, 68.21; H,                                                                6.06; N, 14.04;                                                                C, 68.34; H,                                                                   6.12; N, 13.93; A         - 250                                                                                                                                 142-144                                                                      Light-purple                                                                   crystals C.sub.18                                                              H.sub.20 FN.sub.3                                                              O  C, 68.99; H,                                                                6.43; N, 13.41;                                                                C, 69.23; H,                                                                   6.41; N, 13.31; A         - 251                                                                                                                                 131-132                                                                      Light-red  powder                                                              C.sub.15 H.sub.16                                                              N.sub.2 O  C,                                                                  74.97; H, 6.71;                                                                N, 11.66;  C,                                                                  75.07; H, 6.75;                                                                N, 11.55; I                                                                      - 252                                                                          173-174                                                                      Colorless                                                                      crystals C.sub.18                                                              H.sub.21 N.sub.3                                                               O  C, 73.19; H,                                                                7.17; N, 14.23;                                                                C, 73.08; H,                                                                   7.41; N, 14.18; A         - 253                                                                                                                                 133-134                                                                      Light-purple                                                                   crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.58; H,                                                                   6.88; N, 14.95; A         - 254                                                                                                                                 167-168                                                                      Light-yellow                                                                   crystals C.sub.15                                                              H.sub.15 N.sub.3                                                               O  C, 71.13; H,                                                                5.97; N, 16.59;                                                                C, 71.09; H,                                                                   6.06; N, 16.66; A         - 255                                                                                                                                 176-177  Blue                                                                crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O  C, 71.89; H,                                                                6.41; N, 15.72;                                                                C, 71.75; H,                                                                   6.50; N, 15.76; A         - 256                                                                                                                                 171-172  Purple                                                               crystals                                                                      C.sub.16 H.sub.17                                                              N.sub.3 O  C,                                                                  71.89; H, 6.41;                                                                N, 15.72;  C,                                                                  71.93; H, 6.67;                                                                N, 15.71; A                                                                      - 257                                                                          189-191  Bluish                                                              green  crystals                                                                C.sub.14 H.sub.15                                                              N.sub.3  C,                                                                    74.64; H, 6.71;                                                                N, 18.65;  C,                                                                  75.09; H, 6.77;                                                                N, 18.64; A                                                                      - 258                                                                          225-230                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O.sub.2  C,                                                                    67.83; H, 6.05;                                                                N, 14.83;  C,                                                                  68.00; H, 6.29;                                                                N, 14.83; A                                                                      - 259                                                                          216-217                                                                      Colorless                                                                      crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O.sub.2  C,                                                                    68.67; H, 6.44;                                                                N, 14.13;  C,                                                                  68.80; H, 6.66;                                                                N, 14.14; A                                                                      - 260                                                                          133-135                                                                      Colorless                                                                      crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O.sub.2  C,                                                                    67.83; H, 6.05;                                                                N, 14.83;  C,                                                                  67.87; H, 6.27;                                                                N, 14.81; A                                                                      - 261                                                                          179-181                                                                      Light-brown                                                                    crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O.sub.2  C,                                                                    68.67; H, 6.44;                                                                N, 14.13;  C,                                                                  68.43; H, 6.44;                                                                N, 13.86; A                                                                      - 262                                                                          200-201                                                                      Light-pink                                                                     crystals C.sub.16                                                              H.sub.17 N.sub.3                                                               O  C, 71.89; H,                                                                6.41; N, 15.72;                                                                C, 71.81; H,                                                                   6.40; N, 15.52; A         - 263                                                                                                                                 202-204                                                                      Light-blue                                                                     crystals C.sub.17                                                              H.sub.19 N.sub.3                                                               O  C, 72.57; H,                                                                6.81; N, 14.94;                                                                C, 72.37; H,                                                                   6.79; N, 14.57; A         - 264                                                                                                                                 150-151                                                                      Colorless                                                                      crystals C.sub.13                                                              H.sub.13 N.sub.3                                                               O  C, 68.70; H,                                                                5.77; N, 18.49;                                                                C, 68.63; H,                                                                   5.81; N, 18.34; A         - 265                                                                                                                                 143-144                                                                      Colorless                                                                      crystals C.sub.14                                                              H.sub.15 N.sub.3                                                               O  C, 69.69; H,                                                                6.27; N, 17.41;                                                                C, 69.57; H,                                                                   6.26; N, 17.33; A         - 266                                                                                                                                 212-213  White                                                               powder C.sub.13                                                                H.sub.9 N.sub.3                                                                C, 75.35; H,                                                                   4.38; N, 20.28;                                                                C, 75.34; H,                                                                   4.47; N, 20.08;        __________________________________________________________________________                                                             H                 

TEST EXAMPLES

The following are the results of pharmacological tests of some representative species, which demonstrate the usefulness of the compound of the invention.

Test Example 1 Cystometrography(rats)

Cystometrography is a method for ascertaining the relation between intravesical pressure and bladder capacity and provides information on the time course of condition of the urinary bladder from urine filling to micturition, the possible involuntary contraction of the urinary bladder, and the contractility of the detrusor muscle during micturition.

The experiment was performed using 9 to 13-weeks old female SD rats in groups of 3-5. After a median incision was made in the abdominal region under urethane anesthesia, a polyethylene indwelling cannula was inserted into the urinary bladder dome through the apex of the urinary bladder and fixed. The other end of the cannula was connected to a T-tube for infusion of saline via one branch and changes in intravesical pressure were recorded via the other branch. When warmed saline was continuously infused into the urinary bladder at a constant rate, the urinary bladder was distended and, when the pressure reached a threshold, the urinary bladder underwent rapid contractions and at the same time a micturition was induced. This procedure was repeated until the volume of saline from the start of infusion to the threshold intravesical pressure (bladder capacity) became steady giving approximately constant values in at least two consecutive determinations. Then, the test compound was administered into the duodenum. The bladder capacity was measured immediately before administration of the test compound and 0.5, 1, 2, and 3 hours after administration. The maximum increase rate (%) in bladder capacity was calculated by means of the following equation.

Maximum increase rate in bladder capacity=[(A-B)/B]×100

where B represents the bladder capacity value immediately before administration of the test compound and A represents the maximum bladder capacity at 0.5, 1, 2, and 3 hours after administration of the test compound. Results of the test are shown in Table 3. The data shown are mean values.

                  TABLE 3                                                          ______________________________________                                         Cystometrography (rats)                                                                         Dosage  Maximum increase rate (%)                               Compound No. (mg/kg) in bladder capacity                                     ______________________________________                                         R1            3      63.6                                                         1  3 60.8                                                                      8 30 55.4                                                                     15 10 53.8                                                                     41 10 38.8                                                                     63  3 49.9                                                                     Propiverine 100  42.0                                                        ______________________________________                                          (Compound No. corresponds to that in Table 1 or 2)                       

The compounds of the invention produced equivalent or more potant effect in the increase of bladder capacity at markedly lower dose levels as compared with the reference prior art drug.

It is clear from the above results that the compounds of the invention have potent bladder capacity increasing activity.

Test Example 2 Acute toxicity test

Male ddY mice, 6 to 7-weeks old, were used in groups of 4-5. The animals fasted from the previous day (16-18 hours before the experiment) were given the test compound by oral gavage using a gastric tube and monitored for death for 2 weeks.

As shown in Table 4, no death was encountered at all, nor was observed any abnormal finding.

                  TABLE 4                                                          ______________________________________                                         Acute toxicity test in mice                                                                        Dosage                                                       Compound No. (mg/kg) Dead/Total                                              ______________________________________                                         R1              1000    0/4                                                       1 1000 0/4                                                                     8 1000 0/4                                                                    41 1000 0/5                                                                    63 1000 0/5                                                                  ______________________________________                                    

FORMULATION EXAMPLE 1 Tablets (oral dosage form)

In 200 mg per tablet:

    ______________________________________                                         Compound No. R1     20 mg                                                        Corn starch 88 mg                                                              Crystalline cellulose 80 mg                                                    Carboxymethylcellulose calcium 10 mg                                           Light silicic anhydride  1 mg                                                  Magnesium stearate  1 mg                                                     ______________________________________                                    

A powdery mixture of the above composition was compressed to provide oral tablets.

FORMULATION EXAMPLE 2 Tablets (oral dosage form)

In 200 mg per tablet

    ______________________________________                                         Compound No. 1      20 mg                                                        Corn starch 88 mg                                                              Crystalline cellulose 80 mg                                                    Carboxymethylcellulose calcium 10 mg                                           Light silicic anhydride  1 mg                                                  Magnesium stearate  1 mg                                                     ______________________________________                                    

A powdery mixture of the above composition was compressed to provide oral tablets.

FORMULATION EXAMPLE 3 Tablets (oral dosage form)

In 200 mg per tablet:

    ______________________________________                                         Compound No. 63     20 mg                                                        Corn starch 88 mg                                                              Crystalline cellulose 80 mg                                                    Carboxymethylcellulose calcium 10 mg                                           Light silicic anhydride  1 mg                                                  Magnesium stearate  1 mg                                                     ______________________________________                                    

A powdery mixture of the above composition was compressed to provide oral tablets.

INDUSTRIAL APPLICABILITY

As described above, the compound of the present invention has potent bladder capacity increasing activity with a low toxic potential and is, therefore, useful for the treatment of pollakiuria or urinary incontinence. 

We claim:
 1. A compound of the formula, ##STR333## a salt thereof or a solvate thereof; wherein R¹ is hydrogen or alkoxycarbonylamino; R² is (1) alkyl, (2) aryl which is optionally substituted, (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted, or ##STR334## R⁶ and R⁷ are the same or different and each is (1) hydrogen or (2) alkyl (which alkyl is optionally substituted by (1) hydroxy, (2) aryl which is optionally substituted by alkoxy, or (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole);in case R² is aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted, the aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole is optionally substituted by 1 member or 2-3 different members selected from the group consisting of (1) halogen, (2) alkyl which is optionally substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy is optionally substituted by halogen, aryl which is optionally substituted by alkoxy, or alkoxy), (8) --NHSO₂ R⁸², and (9)--NR⁸³ R⁸⁴ ; or two adjacent substituent groups taken together is --O--(CH₂)_(t) --O--; R⁸² is (1) alkyl or (2) aryl whcih is optionally substituted by alkyl; t is 1 or 2; R⁸³ and R⁸⁴ are the same or different and each is (1) hydrogen, (2) alkyl, or (3) acyl; R³ is cyano or carbamoyl; R⁴ is hydrogen or alkyl; E is alkylene; q is 0 or 1; A is (1) methyl, (2) aryl which is optionally substituted, or (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted; in case A is aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted, the aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole is optionally substituted by 1 member or 2-3 different members selected from the group consisting of (1) halogen, (2) alkyl which is optionally substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy is optionally substituted by halogen, aryl which is optionally substituted by alkoxy, or alkoxy), (8) --NHSO₂ R⁹², and (9) --NR⁹³ R⁹⁴ ; or two adjacent substituent groups taken together is --O--(CH₂)_(u) --O--; R⁹² is (1) alkyl or (2) aryl which is optionally substituted by alkyl; u is 1 or 2; R⁹³ and R⁹⁴ are the same or different and each is (1) hydrogen, (2) alkyl, or (3) acyl;but exclusive of the following cases; (1) R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl, phenyl, or 4-hydroxyphenyl, (2) R¹ as hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, -(E)_(q) -is --CH₂ --, and A is methyl, phenyl, 4-hydroxyphenyl, 4-chlorophenyl, or 4methoxyphenyl, (3) R¹ is hydrogen, R² is diethylamino, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl, phenyl, or 4-bromophenyl, or 3-nitrophenyl, R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, -(E)_(q) - is --CH₂ CH₂ --, and A is methyl, (5) R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is n-propyl, -(E)_(q) - is --CH₂ --, and A is methyl, (6) R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, -(E)_(q) - is --CH(CH₃)CH₂ --, and A is methyl, (7) R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is ethyl, q is equal to 0, and A is methyl, (8) R¹ is hydrogen, R² is methylamino, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl, (9) R¹ is hydrogen, R² is n-butylamino, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl, (10) R¹ is hydrogen, R² is methyl, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is methyl or phenyl, (11) R¹ is hydrogen, R² is methyl, R³ is carbamoyl, R⁴ is methyl, q is equal to 0, and A is methyl, (12) R¹ is hydrogen, R² is methyl, R³ is carbamoyl, R⁴ is hydrogen, q is equal to 0, and A is methyl or phenyl, (13) R¹ is hydrogen, R² is 4-methoxycarbonylphenyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is methyl, (14) R¹ is hydrogen, R² is 4-methoxycarbonylphenyl, R³ is cyano, R⁴ is hydrogen, -(E)_(q) - is --CH₂ --, and A is methyl, (15) R¹ is hydrogen, R² is 2-thienyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is 2-thienyl or 2-furyl, (16) R¹ is hydrogen, R² is 4-nitrophenyl, R⁴ is hydrogen, O is equal to 0, and A is phenyl, (17) R¹ is hydrogen, R² is 2-furyl, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is 2-thienyl or 2-furyl, (18) R¹ is hydrogen, R² is methyl, R³ is cyano, R⁴ is methyl -(E)₁ - is --CH₂ --, and A is methyl.
 2. The compound according to claim 1, a salt thereof or a solvate thereof;wherein R² is ##STR335## R⁶ and R⁷ are the same or different and each is (1) hydrogen or (2) alkyl (which alkyl is optionally substituted by (1) hydroxy, (2) aryl which is optionally substituted by alkoxy, or (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole).
 3. The compound according to claim 1, a salt thereof or a solvate thereof;wherein R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is hydrogen or alkyl, q is equal to 0, and A is (1) aryl which is optionally substituted or (2) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted.
 4. The compound according to claim 1, a salt thereof or a solvate thereof;wherein R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is 2-fluorophenyl, or 2,5-difluorophenyl.
 5. The compound according to claim 1, a salt thereof or a solvate thereof;wherein R¹ is hydrogen, R₂ is NH₂, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl or 4-fluorophenyl.
 6. A pharmaceutical composition for treating pollakiuria or urinary incontinence which comprises a therapeutically effective amount of a compound of the formula, ##STR336## a pharmaceutically acceptable salt thereof or a solvate of them in combination with a pharmaceutically acceptable inert diluent or carrier;wherein R¹ is hydrogen or alkoxycarbonylamino; R² is (1) alkyl, (2) aryl which is optionally substituted, (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted, or ##STR337## R⁶ and R⁷ are the same or different and each is (1) hydrogen or (2) alkyl (which alkyl is optionally substituted by (1) hydroxy, (2) aryl which is optionally substituted by alkoxy, or (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole); in case R² is aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted, the aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole is optionally substituted by 1 member or 2-3 different members selected from the group consisting of (1) halogen, (2) alkyl which is optionally substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy is optionally substituted by halogen, aryl which is optionally substituted by alkoxy, or alkoxy), (8) --NHSO₂ R⁸², and (9)--NR⁸³ R⁸⁴ ; or two adjacent substituent groups taken together is --O--(CH₂)_(t) --O--; R⁸² is (1) alkyl or (2) aryl which is optionally substituted by alkyl; t is 1 or 2; R⁸³ and R⁸⁴ are the same or different and each is (1) hydrogen, (2) alkyl, or (3) acyl; R³ is cyano or carbamoyl; R⁴ is hydrogen or alkyl; E is alkylene; q is 0 or 1; A is (1) methyl, (2) aryl which is optionally substituted, or (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted; in case A is aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted, the aryl, thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole is optionally substituted by 1 member or 2-3 different members selected from the group consisting of (1) halogen, (2) alkyl which is optionally substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (which alkoxy is optionally substituted by halogen, aryl which is optionally substituted by alkoxy, or alkoxy), (8) --NHSO₂ R⁹², and (9) --NR⁹³ R⁹⁴ ; or two adjacent substituent groups taken together is --O--(CH₂)_(u) --O--; R⁹² is (1) alkyl or (2) aryl which is optionally substituted by alkyl; u is 1 or 2: R⁹³ and R⁹⁴ are the same or different and each is (1) hydrogen, (2) alkyl, or (3) acyl.
 7. The pharmaceutical composition according to claim 6, wherein R² is ##STR338## R⁶ and R⁷ are the same or different and each is (1) hydrogen or (2) alkyl (which alkyl is optionally substituted by (1) hydroxy, (2) aryl which is optionally substituted by alkoxy, or (3) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole).
 8. The pharmaceutical composition according to claim 6, wherein R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is hydrogen or alkyl, q is equal to 0, and A is (1) aryl which is optionally substituted or (2) thienyl, benzothienyl, furyl, benzofuryl, dioxolyl, benzodioxolyl or pyrrole which is optionally substituted.
 9. The pharmaceutical composition according to claim 6, wherein R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is methyl, q is equal to 0, and A is phenyl, 2-fluorophenyl, or 2,5-difluorophenyl.
 10. The pharmaceutical composition according to claim 6, wherein R¹ is hydrogen, R² is NH₂, R³ is cyano, R⁴ is hydrogen, q is equal to 0, and A is phenyl or 4-fluorophenyl. 